RESEARCH ANALYSIS

and

UTILIZATION SYSTEM

Contemporary Research in

Pain and Analgesia, 1983

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service • Alcohol, Drug Abuse, and Mental Health Administration
Contemporary Research in

Pain and Analgesia, 1983

Editors:

Roger M. Brown, Ph.D.

Theodore M. Pinkert, M.D., J.D.

Jacqueline P. Ludford, M.S.

National Institute on Drug Abuse

NIDA Research Monograph 45

A RAUS Review Report

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Alcohol, Drug Abuse, and Mental Health Administration

National Institute on Drug Abuse

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For sale by the Superintendent of Documents, U.S. Government Printing Office

Washington, D.C. 20402
NIDA Research Monographs are prepared by the research divisions of the

National Institute on Drug Abuse and published by its Office of Science. The

primary objective of the series is to provide critical reviews of research

problem areas and techniques, the content of state-of-the-art conferences, integrative research reviews and significant original research Its

dual publication emphasis is rapid and targeted dissemination to the

scientific and professional community.

Editorial Advisory Board

Avram Goldstein, M.D.

Addiction Research Foundation

Palo Alto, California

Jerome Jaffe, M.D.

University of Connectiut School of Medicine

Farmington, Connecticut

Reese T. Jones, M.D.

Langley Porter Neuropsychiatric lnstitute

University of California

San Francisco, California

Jack Mendelson, M.D.

Alcohol and Drug Abuse Research Center

Harvard Medical School

McLean Hospital

Belmont, Massachusetts

Helen Nowlis, Ph.D.

Rochester, New York

Lee Robins, Ph.D.

Washington University School of Medicine

St. Louis, Missouri

NIDA Research Monograph Series

William Pollin, M.D.

DIRECTOR, NIDA

Jack Dwell, M.D.

ASSOCIATE DIRECTOR, OFFICE OF SCIENCE, NIDA

 EDITOR-IN-CHIEF

Eleanor W. Waldrop

MANAGING EDlTOR

Parklawn Building, 5600 Fishers Lane, RockviIle, Maryland 20857
Contemporary Research in

Pain and Analgesia, 1983
ACKNOWLEDGMENT

This monograph is based upon papers and discussion from the RAUS

Review Conference on pain and analgesia, held January 19 and 20,

1983, in Rockville, Maryland, sponsored by the Office of Science,

National Institute on Drug Abuse.

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Opinions expressed in this volume are those of the authors and do

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National Institute on Drug Abuse or any other part of the U.S.

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considered essential in the context of the studies reported herein.

Library of Congress catalog card number 83-600612

DHHS publication number (ADM)84-1279

Printed 1983

NIDA Research Monographs are indexed in the Index Medicus. They

are selectively included in the coverage of American Statistics

Index, Biosciences Information Service, Chemical Abstracts, Current

Contents, Psychological Abstracts, and Psychopharmacology Abstracts.

iv
Preface

The Research Analysis and Utilization System (RAUS) is designed to

serve four functions:

Collect and systematically classify the findings of all

intramural and extramural research supported by the

National Institute on Drug Abuse (NIDA)

Evaluate the findings in selected areas of particular

interest and formulate a state-of-the-art review by a

panel of scientific peers;

Disseminate findings to researchers in the field and to

administrators, planners, instructors, and other

interested persons;

Provide a feedback mechanism to NIDA staff and planners so

that the administration and monitoring of the NIDA

research program reflect the very latest knowledge gleaned

from research in the field.

Since there is a limit to the number of research findings that can

be intensively reviewed annually, four subject areas are chosen

each year to undergo a thorough examination. Distinguished

scientists in the selected field are provided with copies of

reports from NIDA-funded research and invited to add any

information derived from the literature and from their own research

in order to formulate a comprehensive view of the field. Each

reviewer is charged with writing a state-of-the-art paper in his or

her particular subject area. These papers, together with a summary

of the discussions and recommendations which take place at the

review meeting, make up a RAUS Review Report in the NIDA Research

Monograph series.

v
In Fiscal Year 1583 the subject of new advances in pain research

was chosen as an area for a RAUS review. This subject has selected

for a comprehensive review because research in the area is funded

by several different NIH and ADAMHA Institutes and there was a need

to bring the findings on the subject together; further, there have

been significant advances in both basic and clinical research on

analgesia but there is a general perception that these have not

been followed by significant advances in general clinical

practice. Finally, there is the basic administrative question as

to whether or not NIDA should continue to fund pain research.

The results of these reviews are presented in this monograph. Drs.

Roger Brown and Theodore Pinkert served as the scientific

moderators of the meeting and the final chapter of this monograph

is their summary of the discussions which took place at the meeting

and the recommendations from the attendees.

vi
Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Executive Summary

Jacaueline P. Ludford . . . . . . . . . . . . . . . . . . . .

Recent Advances in Research on Pain and Analgesia

Howard L. Fields . . . . . . . . . . . . . . . . . . . . . .

Recent Developments in the Neurochemical Bases of Pain and

Analgesia

G. F. Gebhart ........................

Behavioral and Psychological Components of Pain Management

Charles P. O'Brien and Marvin M. Weisbrot . . . . . . . . . .

Biobehavioral Modulation of Pain Transmission

David J. Mayer . . . . . . . . . . . . . . . . . . . . . . .

Mechanisms of Pain and Analgesia as Revealed by Opiate Research:

Summary and Recommendations

Roger M. Brown and Theodore M. Pinkert . . . . . . . . . . .

v

1

3

19

36

46

70

List of NIDA Research Monographs . . . . . . . . . . . . . . . . 76
Executive Summary

Jacqueline P. Ludford, M.S.

Within recent years significant strides have been made in the area of

the neurobiology of pain and analgesia. In particular, the discovery

of endogenous opiates and their receptors has contributed

immeasurably to our understanding of pain transmission and

modulation. At its RAUS review meeting on January 19-20, 1983, NIDA

invited reviewers to discuss:

Anatomy and Physiology of Pain Dr. Howard Fields

University of California,

San Francisco

Neurochemical Basis of Pain Dr. Gerald Gebhart

University of Iowa

Comparative Clinical Studies Dr. Raymond Houde

in Analgesia and Pain Management Sloan-kettering Institute

for Cancer Research

Behavioral and Psychological Dr. Charles O’Brien

Components of Pain Management Veterans Administration

Medical Center, Phila.

Biobehavioral Approach to Dr. David Mayer

Studying Pain Mechanisms Medical College

of Virginia

Dr. Fields’ presentation focused on pain transmission and pain

modulating systems with particular attention to the role of

endogenous opioid peptides. He reviewed the “families” of endogenous

opiates and current knowledge regarding their anatomical sites of

act ion. The probable mechanisms of action of exogenous opiates were

discussed and related to their likely connection with the mode of

action of endogenous opiates. Dr. Fields concluded that

understanding pain modulating systems has greatly contributed to our

understanding of the neural basis of opiate action and vice versa.

1
Dr. Gebhart’s presentation, also in the area of basic neuroscience,

extensively reviewed recent research relative to stimulation-versus

opioid-produced antinociception, starting with the results of focal

electrical stimulation and direct administration of opioids into the

midbrain (1970s). He also reviewed the discovery of opiate receptors

and endogenous opioids and the state-of-the-art in our knowledge

about them as well as the possible implications for analgetic

mechanisms, neuroendocrinologic control, memory, and learning. It is

likely that pain control involves not only endogenous opioid systems

but nonopioid endogenous systems as well, and there was considerable

discussion on this subject. Finally, Dr. Gebhart reviewed research

on the brainstem organization of descending systems of

antinociception. He cited the need for an integrated approach to

pain research, that is, linking behavioral studies with neurochemical

and electrophysiologic investigations.

Dr. houde, who discussed comparative clinical studies in pain

management, has been unable to provide a paper for this monograph.

Dr. Houde focused on the problems of the management of chronic

clinical pain in cancer patients and emphasized the need for better

phannacokinetic studies to determine the optimum balance for dose

effectiveness vs. unwanted effects.

Dr. O’Brien pointed out the paucity of controlled outcome studies to

evaluate the effectiveness of treatment. The significant advances in

understanding the physiology and biochemistry of pain have not yet

been translated into improved pain management at the clinical level.

Dr. O’Brien reviewed the behavioral and psychological aspects of pain

and the potential for some of the less conventional treatments,

including classic conditioning, biofeedback, hypnosis, psychotherapy,

patient-controlled analgesia, antidepressants, and neuroleptic drugs.

Dr. Mayer reported on basic research in the area of behavioral

mechanisms of pain transmission, particularly the environmental

activation of an analgesic system. Using a “footshock” model in

rats, intriguing research has been performed delineating the neural

circuitry and mechanisms involved in pain transmission.

Finally, in the last chapter of this monograph, Drs. Brown and

Pinkert have summed up the discussions that took place over the

course of the two-day meeting and the recommendations for future

research.

AUTHOR

Jacqueline L. Ludford, M.S.

Research Analysis Branch

Office of Science

National Institute on Drug Abuse

Rockville, Maryland 20857

2
Recent Advances in Research

on Pain and Analgesia

Howard L. Fields, M.D., Ph.D.

The past two decades have witnessed remarkable progress in our

understanding of pain mechanisms. Research breakthroughs have

kindled renewed interest in the subject among both neuroscientists

and clinicians. This has produced a marked expansion in the number

of research projects related to the problem of pain. The

increased knowledge and active research in pain have been complemented by similar progress in investigations of the mechanisms of

opiate action. It is a particularly encouraging sign that a broad

cross-section of the biomedical community has been recruited to the

effort. Thus, anatomists, pharmacologists, neurophysiologists,

psychologists, and biochemists as well as clinicians are now

actively involved.

developed.

In a sense, a new field of research has

Progress has been made in two general areas: pain transmission and

pain modulation. I would like just briefly to mention active

research related to transmission and then focus on pain modulation.

PAIN TRANSMISSION

Research has focused on understanding both peripheral and central

mechanisms. It is well established that, in peripheral nerves,

pain is transmitted by small diameter myelinated and unmyelinatea

nerve fibers whose central projections terminate primarily in the

superficial layers of the spinal cord dorsal horn.

The circuitry of the superficial dorsal horn is an area under

active investigation. There is evidence that small diameter

primary afferents terminate on both second-order sensory projection

cells (such as spinothalamic tract cells) and intrinsic interneurons. Some of the interneurons are probably excitatory relay

cells (Bennett et al. 1979) and others are probably inhibitory

interneurons (Gobel 1978). There are numerous interneurons in this

region which contain enkephalin-like immunoreactivity and may be

inhibitory (Hunt et al. 1981).

3
Another important area of research involves the immunocytochemical

study of primary afferents to determine whether they contain

putative peptide neurotransmitters. Small dorsal root ganglion

cells and the superficial layers of the dorsal horn in which they

terminate nave been shown to contain immunoreactive substance P,

somatostatin and vasoactive intestinal peptide (Hokfelt et al.

1980). These findings raise the auestion of whether a particular

peptide is associated with pain-transmitting primary afferents. In

fact, there is an extensive body of evidence indicating that

substance P is contained in nociceptive primary afferents (Henry

1976).

Other recent work has provided evidence identifying particular

classes of primary afferent or central projection neurons as

pain-transmitting using a combination of physiological and

behavioral studies in primates combined with human psychophysical

studies (Lamotte and Campbeli 1978). Unfortunately, a complete

review of the subject is beyond the scope of this paper.

PAIN MODULATION AND THE MECHANISM OF OPIATE ANALGESIA

Accumulated experimental evidence has established that there is a

network Within the brain that functions to selectively inhibit pain

transmission. This network includes neurons at midbrain,

medullary, and spinal levels, some of which contain opioid

peptides. This analgesia system can be activated by narcotic

analgesics such as morphine which presumably mimic the action of

endogenous opioia peptides at synapses where they are normally

released. Thus it is auite clear that advances in our

understanding of the neural mechanisms of pain modulation and

opiate analgesia are closely related.

For example, the identification of the opiate receptor depended on

establishing that there is a similar relationship, in a series of

compounds, between binding-affinity to brain membranes, efficacy on

a bioassay (guinea pig ileum or mouse vas deferens), and analgesic

potency in man (Kosterlitz 1977). Without a consistent and

selective biological effect to guioe research it would not have

been possible to extract and purify the first endogenous opioid

peptides.

On the other hand, once these compounds had been discovered and

sequenced (Hughes et al. 1975, Mains et al. 1977), antibodies to

them were used to map their precise distribution in the brain and

to serve as a guide to the study of pain-modulating systems. This

approach will be discussed in more detail below.

In addition to this direct interdisciplinary interplay between the

study of pain mechanisms and of the action of opiates, the pain

modulation pathway can serve as a model for the cellularneurophysiological mechanisms of opiate action. For example,

evidence, to be discussed below, indicates that there are

4
both presynaptic and postsynaptic. opiatergic synapses that

function in pain modulation. Certainly, tolerance to the analgesic

action of opiates ooes occur and must involve these modulating

systems. As the precise circuitry of these is elucidated, more

sophisticated questions about in vivo tolerance can be posed.

Although it is not certain where future scientific breakthroughs

may come, it is clear thdt research into the neural mechanisms of

opiate action will overlap extensively with that on pain modulation.

Descending Pathways That Control Pain (see previous review, Fields

and Basbaum 1978)

In rats, electrical stimulation of the midbrain periaqueductal gray

(PAG) suppresses pain-related behavior. This suppression appears

to be selective for pain since, during stimulation, the animals are

ambulatory and respond to other types of environmental stimuli.

The existence of this selective pain-suppression system has been

confirmed in a variety of species, but perhaps the most spectacular

confirmation was in human subjects with severe, intractable pain.

Electrical stimulation of the caudal diencephalon and midbrain PAG,

which are analogous to analgesia sites in animals, produces a

dramatic and often complete reduction of pain. The pain

suppression in patients, as in animals, is highly specific. Most

patients note no effects of stimulation besides analgesia, i.e., no

arowsiness, no projected sensation, and no seizures or motor signs

unless the electrode was near oculomotor pathways. The close

anatomical correlation between the effective sites for pain

suppression in man and other species and the Similarity in

behavioral effects of stimulation again suggested that the study of

the animal model would prove highly relevant to human pain.

What is the mechanism of this analgesia? Modulation of pain

transmission could take place at any point from spinal cord to

cortex. Since the spinothalamic tract, or, for that matter, any

proven pain transmission pathway, does not pass throuogh the PAG,

it is unlikely that the suppression actually occurs at the site of

stimulation in the PAG. In fact, lesions restricted to the PAG or

injection of local anesthetic into the PAG does not impair pain

sensation. Thus stimulation of the PAG must cause active

inhibition of pain transmission at some other point in the nervous

system.

These observations established that there is an identifiable pain

suppression system and served as the impetus to search for the

anatomy and physiology of pain suppression. One of the earliest

observations bearing on this problem was that stimulation of

midbrain sites effective for analgesia inhibited spinal

pain-transmission neurons. This indicated that a descending

pathway from brainstem to spinal cord was involved in the pain

suppression. This hypothesis was confirmed by the observation that

partial lesions of the spinal cord at midthoracic levels blocked

analgesia below the lesion. In rats, the effective lesions are

restricted to the dorsolateral funiculus (DLF) (Barton et al.

1980). A large proportion of DLF axons originate in the

5
ventromedial medulla, including the nucleus raphe magnus and the

adjacent reticular formation, and we showed that cells in this

region project specifically through the DLF to terminate in

precisely those regions of the spinal dorsal horn which contain the

neurons responding maximally to painful stimulation (Basbaum and

Fields 1978, Basbaum and Fields 1979). Electical stimulation of

the medullary raphe nuclei powerfully and selectively inhibits pain

transmission neurons in the spinal cord dorsal horn and produces

behavioral analgesia. Thus these raphe nuclei in the medulla

oblongata are a crucial direct link for the modulation of pain.

Subseauent studies have aemonstrated a direct, excitatory

connection from the PAG to the raphe magnus (Behbehani and Fields

1979). More recently, large inputs from frontal cortex, amygdala

am hypothalamus to tne PAG have been demonstrated (Hardy and

Leichnetz 1981, Beitz 1982).

Endogenous Opioid Peptides (Cox 1982)

Endogenous opioid substances are compounds that are synthesized in

the body and have actions similar to narcotic analgesics such as

morphine. The best characterized of the endogenous opioias are the

pentapeptides leucine (leu) and metnionine (met) enkephalin (enk)

and the 30 amino acid compound, beta-endorphin. Leu and met enk

were the first endogenous opioids to be discovered (Hughes et al.

now known to be present in the gut, adrenal medulla, and autonomic 1975). 

They were first extracted from the brain, although they are

flervous system. Beta-endorphin (BE) was first discovered in the

pituitary but has subsequently been shown to be present in the

hypothalamus as well.

Both BE and the enkephalins bind with high affinity to opiate

receptors and both produce analgesia When injected into the

ventricular system. BE is a potent analgesic as are metabolically

stable synthetic enkephalin analogs (e.g. D-Ala-D-leu enk) (Morley

1980).

Peptide transmitters are usually derived from larger precursor

molecules that are synthesized in the cell body. BE is derived

from a large molecule (pro-opiomelanocortin) that is also a

precursor for at least two other biologically active peptides (ACTH

and -MSH) (Mains et al. 1977). Although BE contains the sequence

for met-enk (figure 1), it is not a precursor for the shorter

peptide. The enkephalins have a different precursor

(proenkephalin). BE is present in a single contiguous population

of cells in the diencephalon. Although wiaely distributed in the

brain, neither leu- or met-enk is present in this population of BEcontaining cells.

On the other hand, leu- and met-enk overlap almost completely in

their anatomical distribution. In fact, there is biochemical

evidence, in the adrenal medulla, that leu- and met-enk are derived

from a common precursor (Jones et al. 1982). If this is also

the case in the brain, antibodies to either met- or leu-enk

6
FIGURE 1

SEQUENCES OF ENDOGENOUS OPIOID PEPTIDES

INVOLVED IN PAIN MODULATION

Leucineenkephalin Tyr-Gly-Gly-Phe-Leu-OH

Methionineenkephalin Tyr-Gly-Gly-Phe-Met-OH

ß-endorphin Tyr-Gly-Gly-Phe-Met -Thr-Ser-Glu-LysSer-Gln-Thr-Pro-Leu-Val-Thr-Leu-PheLys-Asn-Ala-Ile-Val-Lys-Asn-Ala-HisLys-Gly-Gln-OH

Dynorphin Tyr-Gly-Gly-Phe-Leu -Arg-Arg-Ile-ArgPro-Lys-Leu-Lys-Try-Asp-Am-Gln-OH

-neoendorphin Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro7
might label all cells that contain the precursor. whether both

enkephalins are released from the same nerve terminals and act

post-synaptically at the same receptor remains an open question.

Another opioid peptide, dynorphin, has recently been discovered

(Goldstein et al. 1981). Dynorphin is a 17 amino acid peptide, the

first five residues of which are leu-enk. Dynorphin is derived

from a third endorphin precursor which also gives rise to

alpha-neoendorphin (Kakidani et al. 1982). Though there is some

overlap (see below), dynorphin’s anatomical aistribution is largely

distinct from that of either BE or the enkephalins.

In summary, there are at least three distinct families of

endogenous opioid peptides. They are coded by separate genes,

occur in different cell groups in the brain, and may have distinct

biological functions. We will focus on the evidence that links

endogenous opioid with the modulation of pain below.

Opiate Receptor and Analgesia

Prior to the characterization of opiate binding sites in the brain,

synthetic modification of the opiate molecule had produced

compounds with a broad range of analgesic potency. Knowledge of

structure-activity relationships, especially of rank-order of

potencies for a number of these opiate agonists, was used to

establish that particular binding sites in the brain were involved

in opiate analgesia (Kosterlitz 1977). Thus it was determined that

the opiate binding site relevant to analgesia is stereospecific and

of high affinity.

It was subsequently demonstrated that brain membrane preparations

show just such high-affinity, saturable, stereospecific binding

sites for opiate agonist and antagonists. Moreover, among a group

of narcotic analgesics there is a positive correlation between

binding affinity and analgesic efficacy. Dextrorotary isomers of

opiates neither bind with high affinity to these sites nor have any

biological activity.

There is now evidence for at least two, and possibly three,

biologically significant binding sites. The two best characterized

binding sites, ‘"mu” and "delta" (d), are defined primarily by

differences in rank order of potency of various opioids to displace

a high affinity labeled ligand from one or the other binding site

(Chang and Cuatrecasas 1979). Available ligands show, at best,

only relative specificity for mu and delta binding sites.

Autoradiographic methods indicate that there is significant

anatomical overlap of mu and delta binding sites (Herkenham and

Pert 1980). It has in fact been suggested that the two binding

sites are physically linked, i.e., that there is a single, two site

receptor (Lee and Smith 1980). Part of the solution of this

problem of linkage of the two binding sites lies in the development

of more specific mu and delta ligands. It could then be determined

whether the location of the two binding sites is identical. Except

8
for the demonstration that certain types of neuroblastoma cell

cultures contain only delta binding sites, it has not been possible

to show clearly that the two binding sites are totally separate.

If there are two binding sites and possibly two distinct receptors,

are their functions different? There is evidence that mu ligands

are potent analgesics. Whether the delta receptor is related to

analgesia is more complex. Both potent analgesia and antagonism of

opioid analgesia have been reported after intracerebroventricular

administration of d ligands. Tung and Yaksh (1982) have recently

shown that, in morphine-tolerant rats, D-ala-D-leu-enkephalin (a

relatively specific delta ligand) remains a potent analgesic. This

suggests that both mu and delta sites are relevant to analgesia.

The existence of the kappa (k) receptor was originally proposed by

Martin (1976) on the basis of distinct actions of the prototype k

agonist, ketocyclazocine. In the chronic spinal dog both morphine

and ketocyclazocine produce miosis and depression of nociceptive

reflexes with sedation, but only morphine causes hypothermia and

bradycardia. With repeated administration, tolerance to both drugs

occurs, and all of these effects are blocked by the antagonists

naltrexone and naloxone. However, when morphine-tolerant dogs are

withdrawn from morphine, ketocyclazocine does not supress the

morphine abstinence syndrome, indicating that the two drugs act at

separate receptors. Further confirmation that the k and mu

receptors are distinct has recently been provided by studies

aemonstrating high affinity selective kappa binding sites

(Kosterlitz and Patterson 1980). Perhaps the most fascinating

aspect of k agonists is that they may have a distinctly higher

analgesic potency on tests of nociception that use mechanical

stimuli (Upton et al. 1982, Tyers 1980). This contrasts with mu

agonists which are more effective than k agonists on tests emloying

noxious heat as the painful stimulus. Perhaps the different

receptor-mediated systems control different modalities of pain

sensation or different types of responses to noxious stimulation.

Support for this hypothesis comes from studies showing that k

agonists produce analgesia largely through a direct spinal action,

whereas systemic morphine’s effect (see below) on spinal

nociceptors has both a supraspinal and a spinal component (Wood et

al. 1981).

Relationship Between Endogenous Opioids and the Intrinsic Analgesia

System (Fields 1982)

The intrinsic analgesia system can be thought of as a discrete

anatomical entity running from the frontal cortex and limbic system

through the periaqueductal gray and ventromedial medulla to the

superficial layers of the dorsal horn. With the possible exception

of the cortex, endogenous opioid peptides are present at all levels

in this system. Enk is present in either cell bodies, terminal

fields, or both, in amygdala, hypothalamus, midbrain periaqueductal

gray, ventromedial meduila (including the serotonergic nucleus

raphe magnus), and in the superficial layers of the dorsal horn.

9

429-538 0 - 84 - 2
Opiate receptor is also present in high concentrations in all these

regions (with the possible exception of the ventromedial medulla

(Herkenham and Pert 1980). BE runs from cell bodies in the

hypothalamus to the amygdala, midbrain periaqueductal gray, locus

coeruleus, and ventromedial medulla.

In recent work Watson and coworkers (1982) have been able to

demonstrate in the rat that although the anatomical distribution

of aynorphin immunoreactivity largely parallels that of leu-enk in

the pain-modulating system, it does differ in some respects.

Dynorphin has a more ventral location in the PAG, and dynorphin cell

bodies are not present in the nucleus raphe magnus or n.

reticularis paragigantocellularis. Whether dynorphin and leu-enk

coexist in some cells is, at present, unknown. Thus all three

known classes of opioid peptides are found in one or more sites

known to be part of the intrinsic analgesia system.

The anatomical association of opioid peptides and opiate receptor

with this pain suppression system taken together with the

well-known analgesic action of opiate alkaloids suggests that the

opioid peptides are crucial for pain modulation under

"physiological" conditions. A major effort has been directed at

confirming this concept and determining how opioid peptides act to

produce analgesia. Experimental strategies have been developed at

several levels; cellular/biophysical, ultrastructural, behavioral,

clinical (subjective), and neurophysiological. A unifying

conceptual thread has been tne use of anatomy, immunocytochemistry,

and pharmacology to relate findings from different types of

experiments.

Microstimulation and microinjection for mapping analgesia-producing

sites. Stimulation-produced analgesia (SPA) gave the first clue

that there is an intrinsic analgesia system. The first region

stimulated was the midbrain periaqueductal gray, which is rich in

enkephalins, BE, and opiate receptor. The midbrain region

effective for SPA extends rostrally into the medial diencephalon.

There is strong evidence that the endogenous opioids in this region

are involved in analgesia; first, SPA from this region is blocked

by the opiate antagonist naloxone. Second, this region is very

sensitive to the analgesia-producing action of locally

microinjected opioids. Third, in man, SPA is associated with a

marked rise in CSF BE-like immunoreactivity (Hosobuchi et al.

1979). Thus, endogenous opioias produce analgesia when injected

into the PAG; they are normally present in the PAG and are released

concomitant with SPA. Further, SPA is blocked by naloxone.

Activation of cells in tne PAG excites cells in the medulla that,

in turn, project to the spinal cord to produce analgesia by

inhibition of pain-transmission neurons (Fields and Basbaum 1978,

Behbenani and Fields 1979). It is of interest that the medullary

region, which contains the pain-modulating relay neurons, is rich

in enk terminals and also has enk-containing cells that project to

the spinal cord (Bowker et al. 1981). Furthermore, in single

10
neurons of this region, coexistence of 5HT with either substance P

or enk has been aemonstratea by double-labeling techniques

(Hokfelt et al. 1978).

If the system outlined above does produce analgesia and if the

enkephalinergic neurons are involved, it should be possible to

produce analgesia by activation of these neurons. We have employed

the method of monopolar microstimulation to produce SPA in the

rostral ventromedial medulla (RVM) (Zorman et al. 1982). In

lightly anesthetized rats, the tail-flick reflex to noxious heat is

present at normal latency and can be blocked by stimulation of the

RVM at intensities of 10 μA (50 Hz, 400 μs pulses, continuous).

Using stimulating currents this low it is possible to state that

the behavioral effects are due to activation of neural elements

within RVM. When low threshold SPA sites in the rostral RVM are

plotted, they overlap with the location of cells projecting via the

DLF to the superficial layers of the dorsal horn.

The use of the microstimulation technique gives a very fine-grained

map of RVM SPA sites, but electrical stimulation is nonselective,

in that any type of locally excitable neural element may be

activated. One approach to this problem is to chemically activate

local neurons. This is done by stereotaxically implanting cannulae

near the target neurons and microinjecting small volumes of fluid.

Opiate microinjection in the RVM does produce potent analgesia

(Akaike et al. 1978, Azami et al. 1982). This strongly suggests

that the anatomically demonstrated enk in the RVM does play a role

in the descending pain-modulating systems.

A very important new approach to experimental studies of pain

modulation was developed by Yaksh and Rudy (1976). They

showed that an intrathecal cannula could be placed at any point

along the spinal cord. Since the descending pain-modulating system

could be activated in brainstem and its action manifest at spinal

levels, the possibility arose of studying the pharmacology of the

pain-modulating system at its output end.

Autoradiographic, immunohistochemical, and biochemical studies have

shown that the superficial layers of the dorsal horn are densely

packed with enk terminals and opiate receptors. Most of the

enkephalin-containing terminals in the superficial dorsal horn

derive from local interneurons. Some of these enkephalin

interneurons have been shown to synapse onto identified

spinothalamic tract cells (Ruda 1982). Opiate microinjection

directly on the cord produces analgesia in animals (Yaksh and Rudy

1976) and in man (Wang et al. 1979). Furthermore, iontophoresis of

morphine or enkephalin into the superficial dorsal horn selectively

inhibits noxious input to dorsal horn cells (Duggan et al. 1976).

There is evidence that opiates produce analgesia, in part, by

acting on opiate receptors located on the terminals of nociceptive

primary afferents. In support of this concept is the observation

that opiates reduce substance P release from dorsal horn tissue in

vitro (Jessell and Iversen 1977) and from cultured dorsal root

11
ganglion cells (Mudge et al. 1979). As of this writing, however,

there are no reports of opioid peptide-like immunoreactivity in the

presynaptic element of an axo-axonic synapse in the dorsal horn of

the spinal cord.

We have proposed tnat medullospinal neurons activate enkephalinergic interneurons which in turn inhibit pain transmission

(Basbaum and Fields 1978). We recently tested this hypothesis by

using the specific opiate antagonist naloxone applied directly to

the spinal cord co reverse SPA from the RVM. A low dose (15-20 μg)

of naloxone reverses SPA when applied to the lumbosacral cord but

not when appliea to the cervical cord. Lumbosacral naloxone also

effectively blocks the analgesia produced by morphine injected into

the fourth ventricle (Levine et al. 1982).

To summarize briefly, endogenous opioid peptiaes are closely

associated with the pain-modulating network at diencephalic,

midbrain, meoullary, and spinal levels. Opiate microinjection at

any one of these levels produces analgesia as does electrical

stimulation of the rostral sites. Several observations indicate

tnat tnis network is activated by systemically administered opiates

to produces analgesia. First, naloxone injected into brainstem

sites reverses the analgesic action of systemically administeted

morphine (Azami et al. 1982). Second, spinal (Barton et al. 1980)

or brainstem (Prouafit and Anderson 1975) lesions markedly reduce

morphine analgesia. Finally, this hypothesis is strongly supported

by the work of Yeung and Rudy (1980) who showed that whereas

microinjection of morphine at either brainstem or spinal cord

produced submaximal analgesia, simultaneous microinjection of

virtually ineffective doses at both sites produces a potent

analgesia. Not only are both structures implicated but this

observation implies that they are interconnected. These results

also imply that understanding the network properties of the

intrinsic analgesia system will be crucial to elucidating the

neural mechanisms of opiate analgesia.

The general approach outlined above has been to study the

behavioral consequences of electrical stimulation of anatomically

defined pathways, and then identify histochemically the component

neurons of the pathway. The final steps are to activate the system

and selectively block peptiaergic neurons by local injection of

antagonists or to mimic their action by local application of

agonists. The results strongly implicate particular groups of

opioid peptide-containing neurons in pain modulation.

Electrical or chemical stimulation of groups of medullary neurons

may or may not produce behavioral events that are of physiological

significance. Further information on this question can be derived

from recording the activity of neurons in SPA-producing regions.

We have used a technique originally developed for studies of the

motor system (Asanuma et al. 1968). Briefly, using the preparation

described above, the metal micro-electrodes can be used for mapping

SPA sites and then for extracellular recording of neurons at those

sites.

12
We have mapped receptive fields for neurons in analgesia-producing

sites in RVM using physiological stimuli such as brushing, tapping,

pinching with toothed forceps, and noxious heat. The activity of

most of the cells in this region is significantly affected by

intense stimuli (either increasing or decreasing their discharge),

and many increase or decrease their discharge when morphine

(5mg/kg) is injected systemically (see Gebhart 1982 for review).

It is now clear that in awake-behaving rats noxious stimuli or

stress can activate the opioid-mediated descending analgesia

network. This indicates that the system can act under

“physiological” conditions. It would be important to show that the

activity of RVM neurons is increased under various conditions that

produce analgesia; for example, during stress and when morphine is

given.

ENDOGENOUS OPIOIDS AND PAIN MODULATION IN MAN

It is important to demonstrate that the endorphin-mediated

analgesia system is operative in man under physiologica

conditions. The usual experimental approach to this problem has

been to give the opiate antagonist naloxone and look for a

worsening of pain. Lasagna (1965) presented the first data

suggesting that naloxone causes hyperalgesia, out conflicting

reports appeared (El-Sobky et al. 1977, Grevert and Goldstein

1977). The method of pain evaluation that we have used is very

simple: subjective pain is reported using the visual analog scale

(a 10 cm line with 0 pain on the right and “worst pain ever” on the

left.) Using this method and a double-blind crossover design

produces a significant increase in reported pain severity compared

to placebo (Levine et al. 1978a). The effect in this clinical

situation requires a relatively higher dose of naloxone (8 mg i.v.

per patient) than is usual for treating narcotic overdose (0.4-0.8

mg) .

Although the naloxone hyperalgesia described above is seen when

data from indiviauals are pooled, more striking changes are

revealed when subjects are categorized. Thus, we have presenteo

evidence that naloxone produces significant hyperalgesia in placebo

responders, but has no effect in placebo non-responders (Levine et

al. 1978b). Furthermore, consistent with our neuropnysioioglcal

studies, there is some evidence that a positive placebo response

(which may represent activation of the endorphin-mediated analgesia

system (EMAS) ) is more likely to occur in patients reporting more

severe pain levels just prior to receiving a placebo (Levine et al.

1979).

Other manipulations whicn have been reportea to produce

naloxone-reversible analgesia include acupuncture (Mayer et al.

1977) and transcutaneous electrical stimulation (Sjolund and

Eriksson 1979).

It should be stressed that the use of naloxone provides only

indirect evidence that a function is mediated by endogenous opioid

peptides. Naloxone may have actions unrelated to opiate

13
antagonism. Other approaches that can be used are to look for

cross-tolerance between opiates and the analgesic manipulation in

question, to look for endogenous opioid peptide release concomitant

with analgesia, and to determine whether the anatomical substrate

that underlies the analgesia produced by that manipulation is

associated with endogenous opioid peptides.

CONCLUSION

The past decade has seen major advances in our understanding of

pain. Most of this advancement has been due to the related

discoveries of an endogenous pain-modulating system and of the

endogenous opioid peptides that contribute to its function. The

explosion of knowledge in this field is the result of a convergence

of different approaches and scientific disciplines to a set of

related problems that involve the neural mechanism of opiate action.

14
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ACKNOWLEDGMENT

Research supported by a grant (DA-01949) from the National

Institute on Drug Abuse.

AUTHOR

Howard L. Fields, M.D., Ph.D.

Departments of Neurology and Physiology

University of California

San Francisco, CA 94143

18
Recent Developments in

the Neurochemical Bases of

Pain and Analgesia

G. F. Gebhart, Ph.D.

BACKGROUND

Several developments in the recent past have been germinal to

the rapid growth in our understanding of the central sites and

mechanisms of nociception and antinociception. In the early

1970's, focal electrical stimulation and opioids given directly

in the midbrain were demonstrated to be antinociceptive. The

second major advance was the demonstration in the central nervous system of opiate receptors and the subsequent discovery of

endogenous opioids.

Stimulation- and Opioid-Produced Antinociception

The initial stimulus for the recent past productive research

activity in mehanisms of antinociception can be traced to the

report by Reynolds (1969) that focal electrical stimulation in

the midbrain periaqueductal gray matter (PAG) produced an antinociception in rats. The nature of this "stimulation-produced

analgesia" (SPA) was subsequently characterized in non-human

animals in other laboratories (e.g., Gebhart and Toleikis 1978,

Lewis and Gebhart 1977a, Mayer and Liebeskind 1974, Oliveras et

al. 1974) and shortly thereafter extended to and successfully

employed in man for the relief of pain (e.g., Hosobuchi et al.,

1977). Stimulation in the PAG also inhibits the ncciceptive

responses of spinal cord dorsal horn neurons (Carstens et al.

1979, 1980, Liebeskind et al. 1973, Oliveras et al. 1974) and it

is generally held that such descending inhibition is necessary

to the antinociception evoked in the brain stem (cf. Fields and

Basbaum 1978). In both the behavioral and electrophysiologic

studies, the data have been generally interpreted to provide

evidenoe for the selectivity of the effects of electrical stimulation for ncciception and nociceptive neurons, respectively.

There is some disagreement on this point, however, since stimulation at sites in and around the PAG which inhibit spinal

19
nociceptive responses do not produce an antinociception or are

aversive in the behaving animal. For example, Liebeskind et al.

(1973) reported early on that the distribution of stimulation

sites in the midbrain of the cat which inhibit spinal nociceptors was wider than the distribution of stimulation sites from

which an antinociception could be produced, including two sites

in the midbrain which produced aversive responses when stimulated. In the behaving animal, SPA is generally considered not to

produce a generalized sensory, motivational, attentional or

motoric deficit (Mayer et al. 1971, Mayer and Liebeskind 1974,

Yeung et al. 1977); that is, the antinociception is considered

to be selective. This interpretation is supported by reports

indicating that SPA is often expressed as an anatomically

restricted field of hypoalgesia (Mayer and Liebeskind 1974,

Soper 1976, Soper and Melzack 1982) and also that animals are

capable of performing other motivated behaviors during SPA

(Soper 1976).

Tsou and Jang (1964) were the first to report that an opioid

(morphine) microinjected into brain tissue produced an antinociception. After a delay of several years (and after the initial

report on SPA), other laboratories characterized the distribution of sites in the brain where opioids were antinociceptive

(e.g., Lewis and Gebhart 1977a, Yeung et al. 1977) and it was

established that the antinociception produced by morphine microinjected into the PAG was a specific opioid effect. The microinjection of other non-opioid, central nervous system depressants (e.g., pentobarbital, chlordiazepoxide) and of local anesthetics was found not to influence nociceptive behavior in a

variety of analgesiometric tests (Lewis and Gebhart 1977a, Yaksh

and Rudy 1978). Following these reports, the antinociception

produced by stimulation and opioids given in the PAG was compared and it was demonstrated that stimulation-produced and opioid-induced antinociception shared many common characteristics

(cf. Mayer 1975, Mayer-and Price 1976, Watkins and Mayer 1982):

- antinociceptive tolerance to the repetitive administration

of morphine or stimulation in the PAG (cf. Mayer and Price

1976);

- development of cross-tolerance between stimulation and morphine given in the PAG (Mayer and Hayes 1975; however, see

Lewis and Gebhart 1977b);

- partial antagonism of SPA by the opioid antagonist naloxone

(cf. Watkins and Mayer 1982); and

- additivity of sub-antinociceptive doses of morphine with SPA

(Samanin and Valzelli 1971).

Reports of these findings spawned neuroanatomic and neurophysiologic investigations revealing that there existed only limited

direct spinopetal efferents from the PAG and that the ventromedial medullary raphe nuclei and adjacent areas were important

to the antinociception and descending inhibition evoked from the

PAG. Thus, it was generally believed that the effects of morphine and stimulation given in the PAG were exerted via a relay

in the medulla; the medullary area most prominently implicated

was the nucleus raphe magnus (NRM) (cf. Basbaum and Fields 1978,

20
1980, Fields and Basbaum 1978, 1979). It was demonstrated that

focal electrical stimulation in the NRM produced an antinociception (Oliveras et al. 1975, 1979) and, like stimulation in

the PAG, also inhibited the nociceptive responses of spinal cord

dorsal horn neurons (Deal) et al. 1976, Fields et al. 1977,

Guilbaud et al. 1977). Further, it was demonstrated that

neurons in the NRM were excited by morphine, glutamate, and

electrical stimulation given in the PAG (Behbehani and Fields

1979, Fields and Anderson 1978, Lovick et al. 1978, Mohrland and

Gebhart 1980a). This led to proposals that the PAG and NRM were

nodal points in an endogenous antinociception-producing system,

and that the antinociception evoked in the PAG relied on a medullary relay in the NRM. The ultimate expression of the antinociception fmn the brain stem was considered to be dependent

upon the spinopetal efferents of the NRM carried in the spinal

cord dorsolateral funiculus (DLF) (cf. Fields and Basbaum 1979).

Since the NRM, like other raphe nuclei, is rich in serotonincontaining neurons, and since there are serotonergic projections

from the PAG-dorsal raphe to the NRM (cf. Fields and Basbaum

1979, Gebhart 1982, Willis 1982), serotonin was considered to be

the primary transmitter involved in this descending antinociceptive system. This interpretation was consistent with a large

earlier body of literature implicating serotonin in the antinociception produced by morphine (cf. Messing and Lytle 1977)

and also with data suggesting the modulation by serotonin of SPA

(cf. Besson et al. 1981). Further, because the opioid antagonist naloxone attenuated the antinociception produced by stimulation either in the PAG or NRM (e.g., Zoman et al. 1981,

1982), an enkephalinergic synapse was believed to be present

between the PAG and NRM or in the spinal cord dorsal horn

between descending serotonegic raphe-spinal fibers and primary

afferent nociceptive input.

The preceedihg is a superficial overview of events leading up to

the topic of this essay. The material is reviewed in greater

depth in several other sources (e.g., Gebhart 1982, Mohrland

1982, Willis 1982).

Opiate Receptors and Endogenous Opioids

The second major development in this field was the demonstration, in the central nervous system, of selective, stereospecific, saturable and reversible binding sites for opiates (Pert

and Snyder 1973, Simon et al. 1973, Terenius 1973). Although

then already called "opiate receptors," it was not until more

recently that these binding sites have been accepted to be in

fact receptors; that is, that a pharmacologic effect results

fran the binding of an opioid to these sites. These receptors

were demonstrated to be localized in areas of the central

nervous system important to nocieption/antinociception (as well

as in other areas of the central nervous system and in smooth

muscle associated with the non-analgetic effects of opioids).

It is now believed that there are as many as six subclasses of

opiate receptors, the more important ones are named mu, delta

2 1
and kappa. These different opiate receptors are heterogeneously

distributed in the central and peripheral nervous systems and

are considered to subserve different roles for different opioid

agonists. Further discussion is beyond the scope of this essay;

specific information is available elsewhere (e.g., Miller 1981,

Wood 1982).

Complementing the demonstration of opiate receptors in the mammalian CNS was the discovery of endogenous opioid-like peptides

in brain (Hughes 1975, Simantov and Snyder 1976). These pentapeptides were subsequently characterized and named methionineenkephalin and leucine-enkephalin. It is now believed that

there are at least 3 different families of endogenous opioids:

the.enkephalins, endorphins and dynorphins/neo-endorphins. The

endorphin family is derived fran the large precursor proopiamelanocortin which is also the parent protein for adrenocorticotropin and melanocyte-stimulating hormones. The cell bodies of

origin of the endorphins are localized in the medial basal hypothalamus which, in addition to giving rise to intracerebral

endorphinergic fibers (to the PAG, for example), send the majority of fibers to the pituitary fran which the endorphins are

liberated (cf. Miller 1981). Although the pentapeptide methionine-enkephalin sequence is contained within the 91 amino acid

ß-endorphin peptide, leucine- and methionine-enkephalin are

derived fran a separate pro-enkephalin precursor and not as

breakdown products of ß-endorphin. The enkephalins, moreover,

are distributed differently fran the endorphins and exist separately. For example, hypophysectomy will significantly reduce

levels of endorphins, but fails to affect the central nervous

system content of enkephalins (Krieger et al. 1977). The final

endogenous opioid family, the dynorphins/neo-endorphins, is less

well understood at present than either the endorphins or enkephalins. The leucine-enkephalin sequence is present at the N terminus of dynorphin-(1-13) and -(1-17), but the enkephalins are

not considered to be derived from the dynorphins. Dynorphin-(1-

13) is a very potent opioid in some systems (Goldstein et al.

1979), but unlike the enkephalins and endorphins it does not

produce an antinociception when administered directly in the PAG

(Walker et al. 1980). The function of the dynorphins, and for

that matter the enkephalins and endorphins, is not well understood at present. It has been hypothesized that the enkephalins

participate generally in the inhibition of release of a variety

of other neurochemicals (e.g., acetylcholine. substance P. thyrotropin-stimulating hormone and that this enkephalinergic

modulation occurs via an inhibitory interneuron acting presynap

tically in the central nervous system (cf. Nicoll et al. 1980).

CURRENT UNDERSTANDING OF THE NEUROCHEMICAL MEDIATION OF ANTINOCICEPTION

It is presently clear that endogenous enkephalins and the monoamines norepinephrine and serotonin are involved in the antinociception evoked in the brainstem either by stimulation or the

microinjection of morphine. Further, there appear to be

22
multiple systems for the production of "analgesia" in which the

same as well as other neurochemicals may be involved (Watkins

and Mayer 1982, Mayer, this volume). The remainder of this

essay will discuss the neurochemicals possibly involved in the

antinociception evoked from the brainstem and recent develop

ments in our understanding of the organization in the brainstem

of descending systems of antinociception.

Neurochemicals and Antinociception

The conclusion drawn from initial studies was that descending

fibers of the serotonin-containing neurons of NRM were necessary

to morphine induced antinociception. This conclusion was based

on studies in which the NRM was destroyed electrolytically; the

antinociceptive efficacy of systemically administered morphine

was significantly attenuated in these studies (Chance et al.

1978, Proudfit and Anderson 1975, Yaksh et al. 1977). Recent

investigations, however, have questioned the role played by the

NRM and serotonergic raphe-spinal neurons in the antinociception

produced by morphine (e.g., Proudfit 1980, Proudfit and Hammond

1981). Thus, it has been suggested that serotonin in the NPM

may not be necessary for the expression of morphine-induced

antinociception. This is further supported by reports that the

neurotoxic (5,7-dihydroxytryptamine) destruction of the serotonin-containing neurons in the NRM does not affect morphineinduced antinociception in some analgesiometric tests (e.g.,

tail-flick), while the efficacy of morphine in the hot-plate

test is unaffected (Mohrland and Gebhart 1980b, Pert et al.

1980). It is now clear that morphine exerts central antinociceptive actions at both the spinal and supraspinal levels (cf.

Yaksh and Rudy 1978, Yaksh 1981) and thus the central level of

organization of the response to nociceptive input is important

to the results reported. Alternatively, transmitters of raphe

spinal neurons other than serotonin are important. Initially,

serotonin and substance P ware shown to co-exist in the same

neurons in the NRM (Chan-Palay et al. 1978, Hokfelt et al.

1978). Consequently, consideration was given to the involvement

of substance P in the antinociception evoked fron or through the

NRM. Supportive evidence was provided by the report that systemically administered morphine increased the content of substance P in the NRM, but did not affect the content of either

serotonin or its metabolite, 5-hydroxyindole acetic acid

(Lakoski et al. 1980). It was suggested, therefore, that morphins had a selective effect on different types of neurons in

the NRM. Additional support for a role for substance P in antinociception is provided by reports that substance P produces an

antinociceptive effect when given systemically, intraventricularly, intrathecally or in the PAG (Doi and Juma 1982, Malick

and Goldstein 1978, Mohrland and Gebhart 1979). The role of

substance P in a descending antinociceptive system remains

uncertain, however, and is complicated by convincing data suggesting that substance P is a transmitter of small diameter

primary afferent (nociceptive) fibers in the spinal dorsal horn

(cf. Jessell 1981).

23
The picture is further complicated by recent reports of the

presence of other peptides in the medial medulla, some existing

independent of and others existing together with serotonin. It

has been recently estimated that 85% of the neurons of the

raphe-spinal system of the rat CNS contain serotonin; approximately half of those serotonin-containing neurons also contain

substance P, while approximately 15% contain thyrotropin-stimulating hormone or enkephalin in addition to serotonin (Rocker et

al. 1982). It is estimated that the remaining 15% of the

neurons of the raphe-spinal system contain either substance P,

thyrotropin-stimulating hormone, enkephalin, acetylcholine, or

other peptides, but not serotonin. The distribution of these

peptides is not homogeneous in the medulla, and it is concluded

from such anatanical evidence that multiple transmitter complexes exist in the medulla, the functions of which are presently

unknown

In addition to serotonin and peptides in the medulla, norepinephrine is also present in descending systems from the brainstem

to the spinal cord and is implicated in the modulation of nociceptive processing (cf. Yaksh et al. 1981). For example, norepinephrine as well as serotonin is released in the lumbar spinal

CSF by morphine and electrical stimulation given in the PAG

(Yaksh 1979, Yaksh and Tyce 1979). Further, both norepinephrine

and serotonin produce an antinociception when administered

intrathecally (Reddy and Yaksh 1980, Yaksh and Wilson 1979) and

also significantly attenuate the noxious-evoked responses of

dorsal horn neurons when administered iontophoretically (Belcher

et al. 1978, Headley et al. 1978, Randic and Yu 1976). Monoaminergic involvement in nociception/antinociception in the

spinal cord is also supported by studies employing pharmacologic

antagonism of presumably post-synaptic monoaminergic receptors.

The intrathecal administration of serotonergic (e.g., methysergide) or noradrenergic (e.g., phentolamnine) antagonists partially attenuates the antinociception produced by morphine

microinjected in the PAG (Yaksh 1979, Yaksh et al. 1976). That

both norepinephrine and serotonin independently play a role is

supported by the complete antagonism of morphine's effect when

both antagonists are given concurrently (Yaksh 1979). Additional data suggesting a separate role for norepinephrine

include reports that -adrenergic agonists (e.g., clonidine) are

antinociceptive when administered in the NRM (Sagen and Proudfit

1982) and intrathecally (Reddy and Yaksh 1980, Reddy et al.

1980). The antinociception produced by serotonin and

-agonists is not antagonized by the opiate antagonist naloxone

(cf. Yaksh et al. 1981). Additionally, the antinociception

produced by the intra-NRM administration of the noradrenergic

antagonist phentolamine was antagonized by the intrathecal

administration of the serotonergic antagonist methysergide

(Hammond et al. 1980). Taken together, such data indicate that

both norepinephrine and serotonin are involved in antinociceptive mechanisms at both spinal and supraspinal levels and may

function independently of enkephalinergic "systems." Indeed,

Tyce and Yaksh (1981) suggest that norepinephrine and serotonin

24
participate in an intrinsic non-opioid system capable of modulating nociceptive transmission. This hypothesis derives from

studies in the cat where peripheral nerve stimulation at intensities activating high threshold A and C "pain" fibers was

demonstrated to significantly increase the content of both monoamines in superfusates of the spinal cord; "non-noxious" peripheral nerve stimulation was without effect on the contents of

norepinephrine and serotonin in the spinal cord superfusates.

The effects of somatic stimulation were unaltered by naloxone,

again indicating that monoaminergic systems which may be

involved in the processing of nociceptive information may exist

independently of, as well as perhaps in concert with, opioidmediated systems.

Data from studies examining SPA suggest a similar conclusion.

Focal electrical stimulation in both serotonin- and norepinephrine-containing cell groupings in the brainstem has been repeatedly reported to be antinociceptive (cf. Besson et al. 1981,

Oliveras et al. 1979, Willis 1982). Not only have norepinephrine, serotonin, and endogenous opioids been implicated in SPA

evoked from the PAG, dopamnine has also been suggested to contribute to the antinociception produced by stimulation in the PAG

(Akil and Liebeskind 1975). Stimulation in the NPM produces an

antinociception which can be antagonized by metysergide (Satoh

et al. 1980) as well as by naloxone, whether administered

systemically (Zorman et al. 1981) or intrathecally (Zorman et

al. 1982). Stimulation in the medullary nucleus paragigantocellularis in the rat, an area lateral to the NRM, produces an

antinociception which can be blocked by an -adrenergic antagonist (Satoh et al. 1980). Thus, like the antinociception produced by morphine administered in the brainstem, norepinephrine,

serotonin, and opioid-containing systems have all been implicated in the modulation of SPA, suggesting a complex, perhaps

overlapping organization of descending systems of inhibition of

nociceptive transmission (also see later section).

In summary, it is clear that norepinephrine as well as serotonin

plays an important role in the modulation of nociception. The

role of peptides, particularly those which might descend from

supraspinal levels, is less clear. Although there are some

descending enkephalinergic fibers from the medulla to the spinal

cord (Hokfelt et al. 1979), the contents of enkephalins in the

spinal cord dorsal horn are not significantly changed by spinal

cord transection, indicating that the majority of enkephalinergic interneurons and/or terminals in the spinal cord dorsal

horn arise from neurons intrinsic to the cord. Thus, the

involvement of peptides may arise locally in the medulla or

spinal dorsal horn. Further, many other putative modulators of

nociceptive processing have not been considered in this essay.

For example, GABA and/or glutamate may be involved in nocicep

tion and antinociceptive mechanisms in the PAG (Sherman and

Gebhart 1975, 1976). Lovick and Wolstencroft (1983) recently

suggested that GABA is involved in the actions of the NRM in

suppressing the responses of reticular neurons to noxious

25

429-538 0 - 84 - 3
stimulation. There is also a literature detailing the role Ca++

plays in the antinociception induced by morphine; the intracerebroventricular administration of Ca++ reportedly antagonizes

morphine-induced antinociception (Hano et al. 1964; Harris et

al. 1975), and the content of Ca++ in selected brain sites is

increased during the development of tolerance to morphine's

antinociceptive effect (Harris et al. 1976, Yamamoto et al.

1978). Thus, while we know far more today about neurochemical

mediators "participating" in the antinociception induced by

morphine and stimulation, we are still far fran fully understanding the mechanisms involved.

Brainstem Organization of Descending Systems of Antinociception

Until now I have focused upon the NRM as the bulbar relay

between the PAG and the spinal cord responsible for the antinociception and descending inhibition of spinal nociceptive

responses evoked fran the midbrain. However, efferents from the

PAG also distribute to sites both dorsal and lateral to the NRM

in the medulla (cf. Gebhart 1982). As stimulation in the NRM is

antinociceptive and also capable of inhibiting spinal nociceptive neurons, so too does stimulation lateral to the NRM produce

an antinociception or inhibition of noxious-evoked activity of

dorsal horn neurons (Fields and Anderson 1978, Fields et al.

1977, Gerhart et al. 1981, Satoh et al. 1980). While transection of the DLF significantly attenuates the effects of stimulation in the NRM, transections of the DLF do not attenuate the

effects of stimulation lateral to the NRM (Haber et al. 1980,

McCreery et al. 1979). Therefore, it is apparent that at least

two medullary systems of descending spinal inhibition exist.

This helps to explain data suggesting that morphine and stimulation in the PAG may not be affecting the same system of descending inhibition, but rather affecting different systems similarly- For example, lesions bilaterally placed in the medullary

reticular formation on either side of the NRM blocked the antinociception produced by morphine administered in the PAG but not

that produced by stimulation at the same site in the PAG

(Mohrland et al. 1982). In addition, depletion of serotonin and

norepinephrine in the spinal cord failed to affect the efficacy

of SPA evoked fran the PAG, but prevented expression of the

antinociception produced by morphine microinjected in the PAG

(Johannessen et al. 1982).

Stimulation in the PAG can also apparently activate two different systems of antinociception: stimulation in the ventral PAGdorsal raphe produces an antinociception which can be antagonized by naloxone, while stimulation in the dorsal PAG produces

an antinociception which is not antagonized by naloxone (Cannon

et al. 1982). This result helps clarify confusion in the earlier literature regarding the controversy over whether naloxone

antagonized SPA. Regardirg inhibition of nociceptive responses

of dorsal horn neurons, lesions in the NRM alone do not affect

the efficacy of stimulation in the PAG, and recent electrophysiolgic studies suggest that the descending inhibition evoked

26
from the PAG courses in a diffuse manner through the medulla

medially and laterally (Gebhart et al. 1983, Gebhart and

Sandkühler 1983). Thus, the functional organization and the

neurochemical composition of the antinociception-producing/descending inhibitory system(s) is more complex than previously

believed. Collectively, recent reports clearly question the

notion of a single, selective system of descending antinociception and inhibition. They support, instead, the existence of

multiple functionally heterogeneous antinociceptive and inhibitory influences (see also Mayer, this volume). A significant

failing in earlier studies in this field was the absence of

behavioral correlates to either the neurochemical or electrophysiologic indices examined. More investigations are currently

correlating the neurcchemical and electrophysiologic data with

behavioral measures of antinociception. Such integrated

approaches to research problems in this field will help clarify

what now appear to be contradictions or inconsistencies in the

literature.

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34
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ACKNOWLEDGMENT

The author's work is supported in part by Grant No. DA 02879 from

the National Institute on Drug Abuse.

AUTHOR

G.F. Gebhart, Ph.D.

Professor

Department of Pharmacology

University of Iowa

Iowa City, IA 52242

35
Behavioral and Psychological

Components of Pain Management

Charles P. O’Brien, M.D., Ph.D.,

and Marvin M. Weisbrot, M.B.A.

In recent years there have been significant advances in our

understanding of the physiology and biochemistry of pain

perception. Many of these are reviewed elsewhere in this

monograph. However, these advances have thus far not been

translated into improved treatment for the pain patient,

particularly the chronic pain patient. On the whole, our review

indicates that most chronic pain patients are treated by a

combination of behavioral and psycholcgical tehniques which have

not been objectively evaluated for efficacy. Moreover since the

syndrome of chronic pain lacks a generally agreed upon classification system and severity rating system, it is difficult to

reliably test new treatments as they are generated from the

research labs. In this paper, we will review some of the

techniques currently in use and comment upon the need for further

research and evaluation.

BEHAVIORAL

Operant conditioning is believed to underlie a large part of

pain-related behavior. The pain patient receives reinforcement

in the form of attention and sympathy when he indicates the

presence of pain. Fordyce and Steger (1979) nicely describe

thee developement of pain-related behaviors in patients by an

operant mechanism. In a sense the behaviors (moans, grimaces,

limps) can be shaped by the people in the patient's environment.

By the time the patient arrives at a pain clinic these behaviors

may be central to the patient's life. A recommended treatment

strategy in many pain clinics is to utilize operant conditioning

to reshape the patient's behavior. This involves reward or

reinforcement of "pain-incompatible behaviors" and nonreinforccment of pain-related behaviors. Treatment may take the form of

a combined effort by all staff in a day treatment center and it

should involve the training of family members to change their

behavior relative to the patient with pain.

The approach to pain as a learned behavior is reported to be

quite effective in several reports. The treatment has a well

developed rationale and it is widely practiced in many pain

36
clinics. However, in our review we were not able to find any

controlled treatment outcome studies that demonstrated efficacy.

We were not able to find evidence that classical conditioning is

being used in the treatment of pain even though there is

considerable evidence that the effects of opiate drugs are

influenced by classical conditioning. Abraham Wikler (1973)

described what he called counter-adaptive effects which were

learned with reputed exposure to drugs. More recent investigations have shown that tolerance to opiates follows the rules

of classical conditioning with environmental stimuli as the

complex conditioning stimulus. Thus, Siegel (1978) has shown

that opiates given repeatedly in the same environment (so that

environmental cues reliably predict the onset of opiate effects)

produce more tolerance than opiates given in a novel environment

(so that environmental cues fail to predict the onset of opiate

effects). Other investigators (O'Brien et al. 1977) have showm

that opiate withdrawal effects can be conditioned and that, in

some cases, opiate-like effects can be conditioned. others have

shown that both alcohol and neuroleptics can also produce

conditioned effects. Thus it is likely that the effects of many

drugs used in the treatment of pain are influenced by conditioning. Conditioning is an area of research which has been

well supported by NIDA over the years, probably because of its

potential relationship to drug dependence. This phenomenon also

has a relationship to the therapy of pain, but the principles

of classical conditioning have yet to be investigated for

potential usefulness in this area.

BIOFEEDBACK

The feedback of information concerning visceral or somatic

responses, using a visual or audio analog, has been shown to

enable human subjects to gain some degree of control over such

responses. In the treatment of pain, electromyographic (EMG)

biofeedback and temperature biofeedback have been the two

modalities generally used. EMG biofeedback has been reported to

facilitate the learning of muscular relaxation and this has been

reported in several studies to be beneficial in such conditions

as tension headaches, low back pain and temporomandibular joint

pain. Case reports and small patient series are often found in

the literature. For example, Peck and Kraft (1977) reported

significant reduction of pain in twelve of eighteen patients

with tension headaches and in one of eight back pain patients.

They also reported improvement in three headache patients, three

back and shoulder pain patients, and two patients with

tempormandibular joint pain. This interesting report is

typical of the biofeedback and pain literature. Unfortunately,

there is no control group and no attempt to classify patients

other than by the location of their pain.

37
Biofeedback has been used in contexts other than treatment of

pain. For example it has been used in the treatment of anxiety

and phobias as an aid to muscular relaxtion. It has also been

used in the treatment of opiate withdrawal. Some research on

these conditions has utilized control groups using noncontingent

or "false" biofeedback. In these studies it has been found that

there is a very potent nonspecific or placebo effect of biofeedback (Khatami et al. 1982). Moreover, it has been determined

that many people can learn to relax their muscles without the aid

of a biofeedback instrument.

Our review indicated that EMG biofeedback appears to be widely

used in pain clinics throughout this country and it is generally

believed to be effective (Khatami et al. 1979). However,

controlled studies to prove efficacy are lacking. Temperature

biofeedback has also been recommended for the treatment of

migraine headaches. In this treatment, warming of the peripheral

skin of a digit has been reported to be associated with improve

ment in headaches. Using the biofeedback technique the patient

can learn to warm his skin and thus, possibly indirectly, affect

the blood vessels within the brain. It should be noted that

there appear to be significant placebo or nonspecific effects

in this treatment and the actual efficacy remains uncertain. Of

course, placebo effects can be quite useful in the treatment of

pain and if it is determined that the use of elaborate and

impressive biofeedback equipnent results in enhanced placebo

effect, this is not necessarily a bad result. Unfortunately the

literature seems to contain mainly anecdotal reports rather than

controlled studies. Thus, distinctions between placebo effects

and specific effects are difficult to make.

HYPNOSIS

Hypnosis is another technique which is frequently used as part

of a comprehensive treatment program for the management of pain.

There is ample evidence, from numerous experiments over the

years, that hypnosis can relieve pain at least temporarily. The

mechanism is uncertain, but two studies (Goldstein and Hilgard

1975; Barber and Nayer 1977) have found that naloxone failed

to reverse hypnotic analgesia, suggesting that the endorphin

system was not involved in those cases. In one report, naloxone

did reverse hypnotic analgesia (Stephenson 1978). The role of

hypnosis in the management of chronic pain is also not clear.

Several authors have indicated that it is a useful technique in

"good hypnotic subjects," particularly those who can be taught

the technique of self-hypnosis (Barber 1982). Here again,

evidence consists mainly of clinical case reports.

38
PSYCHOTHERAPY

Comprehensive pain clinics usually include a wide variety of

psychotherapeutic techniques. In addition to individual psychotherapy, some form of family or marital therapy is often

included. It is generally thought by clin!icians that the treatment of the pain patient should involve the patient's entire

support system. Family conflicts often can be recognized which

may have resulted from the disability produced by the pain or in

some cases may have antedated the pain. These conflicts may

produce anxiety and depression which aggravate the pain syndrome.

In either case, family or marital therapy would be indicated as

part of the comprehensive pain treatment program.

While psychotherapy is generally a part of the program, the type

of psychotherapy is usually not well specified. Modern psychotherapy research often utilizes manual-guided psychotherapy so

that each patient is receiving a known standard treatment

technique. Manuals are available for supportive psychotherapy

and cognitive-behavioral psychotherapy, two treatments which

appear to be used in many pain clinics. Unless manuals are

used, it cannot be certain that a standard treatment is being

administered.

PSYCHOTHERAPY OF THE PRESCIPTION OF ANALGESICS

It is widely lamented in the medical literature (Angell 1982)

that pain, particularly acute pain, is often undertreated by

physicians. Perhaps many physicians have an aversion to spending

time with patients in pain, trying to understand the nature of

pain and the response or lack of response to treatment. Many

physicians report a fear of producing addiction even in

terminally ill cancer patients. These patients, therefore, are

often undertreated so that they experience unnecessarily severe

pain in their final days. On the other hand, one sees chronic

pain patients who are, perhaps, too readily given potent

analgesics without proper medical management. Clearly there is

a great need for physician education regarding the treatment of

pain.

A recent technical advance which utilizes many of the behavioral

principles involved in pain management is the use of patientcontrolled analgesia (Tamsen et al. 1982). In this method,

patients suffering from acute pain are outfitted with a

programable electric pump which controls intravenous infusions

of morphine or another rapidly acting opioid. The patient is

then able to activate the pump at will, causing the injection of

a small quantity of opioid as needed. There is a tilt-in

latency period, usually five to ten minutes, between injections

39
to prevent the possibility of overdose. Experience thus far with

this technigue indicates that it usually results in a highly satisfactory level of pain relief. Total daily dosage is less

than would occur with the usual"prn intramuscular" dosing, which

is generally controlled by the nurse rather than the patient.

Under the prn system, the patient may request a dose of analgesic

when the nurse comes by, not because medication is really

required, but because he recognizes that the nurse may be too

busy to come promptly later when the medication is really needed.

Controlled evaluations of patient-controlled analgesia are

currently in progress.

The use of analgesics in the treatment of chronic pain presents

quite different problems from usage in acute pain. Many of the

patients presenting at chronic pain clinics already are quite

tolerant to and dependent upon opioid drugs. In these cases the

drugs may be providing relatively little in the way of pain

relief, but they may be perpetuating their use through the onset

of withdrawal symptoms as early as 4-6 hours after the last dose

was received. The withdrawal symptoms create discomfort which

is translated into a desire for drug. It is generally felt by 

pain clinics that detoxification is helpful in these cases

(Taylor et al. 1980). One can switch the patient to a long

acting opioid such as methadone. Methadone provides analgesia

for no more than 4-6 hours, but it prevents the onset of withdrawalfor at least 24 hours. A common practice is to utilize a

liquid form of methadone and then graduadlly reduce the dose while

keeping the volume constant. Thus, the patient is not aware of

the timing of each dose decrement although he generally realizes

that one of the goals of treatment is detoxification. Using

this method, there are many case reports indicating that success

is often accompanied by an increase in the patient's feeling of

well-being and even reduction in his concern about pain. While

NIDA has supported several excellent studies on detoxification

procedures from methadone maintenance programs, we were not able

to find any controlled studies of the effects of detoxification

in chronic pain clinics.

PSYCHOACTIVE MEDICATION

Antidepressant drugs, particularly amitriptyline and doxepin, are

frequently used in the management of chronic pain. There is

significant overlap between the syndromes of depression and

chronic pain. several studies have found that 60-65% of

depressed outpatients complain of physical pain (Ward et al.

1982). In pain clinics, a significant minority of patients show

elevated depression scores on various psychological tests, but

we were unable to find any systematic assessment of pain patients

utilizing modern psychiatric nosology such as DSM-III or RDC

40
(Research Diagnostic) criteria. It is possible, therefore, that

some of the patients in pain clinics who appear to be helped by

antidepressant medication are really responding to treatment of

their depressive syndromes. However,there are other postulated

mechanisms.

There is a significant body of literature showing potentiation

of the analgesic effect of opioid drugs by tricyclic antidepressants (TCA). Early work concentrated on antinociceptive activity

of the TCA. Charpentier demonstrated high analgesic activity

produced by TCA in animals in visceral, skin, and trigeminal

areas. Sarnivaara and Mattila (1974) noted that tertiary

tricyclics were inferior to morphine, but superior to secondary

amine TCA in antinoceptive effect. They concluded that this

effect was due either to a local anesthetic effect or a central

serotonergic mechanism rather than any adrenergic or adrenolytic

activity. Chapman and Butler (19781, working with human chronic

pain patients, tested the hypothesis that doxepin has analgesic

properties. Among their conclusions, they stated that the prompt

efficacy of TCA "... is probably not due to the relief of

reactive depression since positive responses are observed

inexplicably early..." Other studies demonstrated enhancement

of propoxyphene analgesia by doxepin (Tofanetti et al. 1977),

potentiation of morphine analgesia by amitriptyline (Liu and

Wang 1981), and enhancement of analgetic effects of morphine

and pentazocine by TCA (Lee and Spencer 1980).

Theories on the mechanism of enhancement were proposed by Malseed

and Goldstein (1979). Antidepressant effects and local analgetic

effects were discounted as major mechanisms (Chapman and Butler

1978; Malseed and Goldstein 1979; Liu and Wang 1981). Possible

biochemical effects would include:

a. Reduction of synaptic release of acetylcholine in the

brain, thereby enhancing the ability of morphine to interfere

with central cholinergic activity.

b. Although the roles of central moncamines in nociception

are not clear, one possiblity is that TCA may have their effect

by interfering with presynaptic uptake and increasing synaptic

concentrations of serotonin, thereby augmenting the effects of

opioids in the central pathways involved in nociception and

enhancing analgesia.

c. TCA are biotransformed by the cytochrome P-450 system in

rat liver, as are morphine and methadone. Further, desmethylimipramine has been shown to inhibit N-demethylation of methadone in

rat liver (Goldstein et al. 1982). Malseed and Goldstein (1979)

have suggested that retardation of hepatic biotransformation of

41

429-538 0 - 84 - 4
morphine by amitriptyline and nortriptyline may occur. Goldstein

et al. (1982) demonstrated increased morphine plasma levels as a

direct outcome of pretreatment with desmethylimipramine. Such

pretreatment also increased peak intensity and duration of

antinociceptive effects of morphine in rats (Liu and Wang 1981).

They proposed that the enhanced analgesia is directly related to

higher plasma levels of morphine causing higher brain

concentrations, since both the plasma level and analgesia

increases occurred simultaneously.

In summary, TCA have been useful in the management of chronic

pain, probably for a variety of reasons. While controlled

studies in nondepressed patients are lacking, clinicians

generally agree that TCA reduce pain or potentiate other

analgesics.

NEUROLEPTICS DRUGS

Nonsedating neuroleptics such as fluphenazine and haloperidol

have been recommended in the treatment of chronic pain. The

mechanism of action here is not at all clear. These drugs have

some antianxiety effect and one point of view is that they

assist in the management of pain by reducing the anxiety

component . They have the advantage of producing less tolerance

than anxiolytic drugs, but they have the disadvantage of having

other more serious potential side-effects. These drugs are dopamine antagonists and they carry the risk of producing tardive dyskinesis. This risk is very small when the drugs are given in low

doses, as they are typically used in pain clinics, but it is still

a risk which must be considered.

MINOR TRANQUILIZERS

Minor tranquilizers, particularly the benzodiazepines, are

generally not recomended in the treatment of pain. While these

drugs do relieve anxiety, which should thus be helpful to pain

patients, tolerance develops to many of their effects. Physical

dependence has been demonstrated in response to all of the minor

tranquilizers that have been studied in this regard. While the

abuse potential of these drugs is low compared to other sedating

drugs such as barbiturates, they do lead to abuse in some

patients.

RESEARCH NEEDS

It is clear from our review of the literature that there are

nUmerous treatments for pain which are being utilized in the

absence of evidence for efficacy. The problem is most noticeable

in the area of chronic pain. While it can be argued that pain

42
is a complex problem which resists the application of controlled

outcome methodology, other equally complicated conditions such

as drug dependence, alcoholism, neurosis, and other psychiatric

disorders have been amenable to treatment outcome research. The

complex treatment programs which are currently applied in the

management of pain wntain many independent elements which could

be studied objectively. If the pattern developing in other areas

applies also to the area of pain, it will be found that there are

some patients for whom a particular treatment element is very

helpful, others for whom it is neutral, and others for whom the

treatment element actually worsens their condition.

In order to correct this situation, we would like to make two 

main recommendations. First, research should be supported which

leads to the development of a classification system for pain

patients. This will involve the development of diagnostic

categories and severity rating scales. These scales will have 

to be subjected to reliability and validity testing utilizing 

large populations of patients and several different investigators. A classification system, however, is necessary in order

to accomplish controlled outcome studies.

A second recommendation is that research support be directed

toward conducting controlled outcome studies. The current

treatment literature on chronic pain is based on clinical

experience and reports of interesting cases. The large sums of

money being spent currently on long and complicated treatments

will eventually have to be justified. Controlled prospective

treatment studies can lead to the selection of the right treatment for a given patient and to the discarding of treatments

which are found to be ineffective. This is also the method by

which potential new treatments coming out of basic research can

be properly evaluated.

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Medicine, 306:98-99, 1982.

Barber,J. Incorporating hypnosis in the management of chronic

pain In: Barber, J., and Adrian, C., eds. Psychological

Approaches to the management of Pain. New York, NY:

Brunner/Mazel, Inc., 1982. pp. 40-59.

Barber, J., and Mayer, D. Evaluation of the efficacy and neural

mechanism of a hypnotic analgesia procedure in experimental

and dental pain. Pain, 4:41-48, 1977.

Chapman, R.C., and Butler, S.H. Effects of doxepin on perception

of laboratory-induced pain in man. Pain, 5:253-262, 1978.

43
Fordyce, W.E., and Steger, J.C. Chronic pain. In: Pomerleau,

O.F., and Brady, J.P., eds. Behavioral Medicine: Theory

 and Practice. Baltimore, MD: Williams & Wilkins, 1979.

pp. 125-153

Goldstein, A., and Hilgard, E. Lack of influence of the morphine

antagonist naloxone on hypnotic analgesia. Proc Natl

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Goldstein, F.J.; Mojaverian, P.; Ossipov, M.H., and Swanson,

B.N. Elevation in analgetic effect and plasma levels of

morphine by desipramine in rats. Pain, 14:279-282, 1982.

Khatami, M.; Woody, G.; and O'Brien, Chronic pain and

narcotic addiction: A multitherapeutic approach - A pilot

study. Comprehensive Psychiatry, 20(1):55-60, 1979.

Khatami, M.; Woody, G.; O'Brien, C.; and Mintz, J. Biofeedback

treatment of narcotic addiction: A double-blind study.

Drug and Alcohol Dependence, 9:111-117, 1962.

Lee, R.L., and Spencer, P.S.J. Effect of tricyclic antidepressants on analgesic activity in laboratory animals.

Postgraduate Medical Journal, 56 (Suppl. 1) :19-24, 1980.

Liu, S.J., and Wang,R.I.H. Increased analgesia and alterations in

distribution and metabolism of methadone by desipramine in

the rat. J Pharm and Exper Therap 195(1):94-104, 1981.

Malseed, R.T., and Goldstein, F.J. Enhancement of morphine

analgesia by tricyclic antidepressants. Neuropharmacology,

(18):827-829, 1979.

O'Brien, C.P.; Testa, T,; O'Brien, T.J.; Brady, J.P.; and Wells,

B. Conditioned narcotic withdrawal in humans. Science,

195:1000-1002, 1977.

Peck, C.L., and Kraft, G.H. Electromyographic biofeedback for

pain related to muscle tension. Archives of Surgery,

112:889-895, 1977.

Saarnivaara, L., and Mattila, M.J. Comparison of tricyclic

antidepressants in rabbits: Antinociception and

potentiation of the noradrenaline pressor responses.

Psychopharmacologia (Berl.) 35:221-236, 1974.

Siegel, S. Tolerance to the hyperthermic effect of morphine in

the rat is a learned response. J of Comp and Physiol

Psychol, 92(06):1137-1149, 1978.

Stephenson, J.B.P. Reversal of hypnosis-induced analgesia by

nalaxone. The Lancet, pp. 991-992, 1978 (ii).

Tamsen, A.; Bondesson, U.; Dahlstrom, B.; and Hartiv, P.

Patient-controlled analgesic therapy, Part III:

Pharmacokinetics and analgesic plasma concentrations of

ketobemidone. Clinical Pharmacokinetics, 7:252-265, 1982.

Taylor, C.B.; Zlutnick, S.I.; Corley, M.J., and Flora, J. The

effects of detoxification, relaxation., and brief supportive

therapy on chronic pain. Pain, 8:319-329, 1980.

44
Tofanetti, O., Albiero, L., Galatulas, I., and Genovese, E.

Enhancement of propoxyphene-induced analgesia by doxepin.

Psychopharmacology, 51:213-215, 1977.

Ward, N.G., Bloom, V.L., Dworkin, S., Fawcette, J.,

Narasimhachari, N., and Friedel, R. Psychobiological

markers in coexisting pain and depression: Toward a

unified theory. J of Clin Psychia 43:32-39, August,

1982.

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the initial effects of drugs. Conditioned Reflex,

8:193-209, 1973.

AUTHORS

Charles P. O'Brien, M.D., Ph.D.,and Marvin Weisbrot, Psychiatry

Service, Philadelphia VA Medical Center and University of

Pennsylvania, University and Woodland Avenues Philadelphia, PA

19104

45
Biobehavioral Modulation

of Pain Transmission

David J. Mayer, Ph.D.

It has been well known for millenia that the perception of pain is

highly vulnerable to environmental manipulations. It is only

within the past few years, however, that systematic examination of

the neurobiological consequences of various environmental

manipulations has generated intense interest. This renewed interest

is probably attributable to major interacting new discoveries in

the fields of pain research and opiate pharmacology. First I will

review the evidence which gave rise to the concept of an endogenous

opiate analgesia system. This includes stimulation-produced

analgesia, the discovery of endogenous opiate peptides, and the

primary neural structures involved (periaqueductal gray matter,

ventral medulla, dorsolateral funiculus, spinal cord dorsal horn).

Then I will discuss the development of experimental attempts to

activate this system with environmental manipulations. These

experiments have shown that painful and/or stressful stimuli are

potent modulators of the transmission of nociceptive stimuli. A

detailed description of the neuroanatomical and neurochemical

circuitry involved in analgesia produced by electrical footshock in

the rat will follow. This work has demonstrated the existence of

multiple pain modulatory systems. Finally an attempt to organize

the rather confusing data in this field will be made, and the

implications of this work for the role of narcotics in the treatment of clinical pain will be discussed.

A simple invariant relationship between stimulus intensity and the

magnitude of pain perception is often not present. This concept

was explicitly embodied in early models of pain perception despite

the lack of direct evidence to support it (Melzack and Wall 1965;

Noordenbos 1959). The impetus for a renewed interest in the

detailed study of pain modulatory circuitry resulted from the

observation that electrical stimulation of the brain could

powerfully suppress the perception of pain (Mayer et al. 1971;

Reynolds 1969). Further investigation of stimulation-produced

analgesia (SPA) provided considerable detail about the neural

circuitry involved. Importantly, several similarities were

recognized between these observations and information emerging from

a concomitant resurgence of interest in the mechanisms of opiate

46
analgesia. The most important parallel facts revealed by these

studies were: 1) Effective loci for both opiate analgesia (OA) and

stimulation-produced analgesia (SPA) lie within the periaqueductal

and periventricular gray matter of the brain stem (Mayer and Price

1976); 2) OA and SPA are both mediated, at least in part, by the

activation of a centrifugal control system which exits from the

brain via the dorsolateral funiculus of the spinal cord (Basbaum et

al. 1977; Murfin et al. 1976); and 3) The ultimate inhibition of

the transmission of nociceptive information occurs at the initial

processing stages in the spinal cord dorsal horn and homologous

trigeminal nucleus caudalis by selective inhibition of nociceptive

neurons (Bennett and Mayer 1979).

In addition to these correlative observations, studies of SPA

produced direct evidence indicating that there are mechanisms

extant in the central nervous system which depend upon endogenous

opiates (Mayer 1980): 1) Subanalgesic doses of morphine were shown

to synergize with subanalgesic levels of brain stimulation to

produce behavioral analgesia (Samanin and Valzelli 1971); 2)

Tolerance, a phenomenon invariably associated with repeated

administration of opiates, was observed to the analgesic effects of

brain stimulation (Mayer and Hayes 1975; Sessle et al. 1975)); 3)

Cross-tolerance between the analgesic effects of brain stimulation

and opiates was demonstrated (Mayer 1975); and 4) SPA could be at

least partially antagonized by naloxone, a specific narcotic

antagonist (Akil et al. 19763). This last observation, in particular, could be most parsimoniously explained if electrical stimulation resulted in the release of an endogenous opiate-like factor

(Mayer 1975). Indeed, naloxone antagonism of SPA was a critical

impetus leading to the eventual discovery of such a factor (Hughes

1975).

Coincidental with work on SPA, another discovery of critical

importance for our current concepts of endogenous analgesia systems

was made. Several laboratories, almost simultaneously, reported

the existence of stereospecific binding sites for opiates in the

central nervous system (Hiller et al. 1973; Pert and Snyder 1973).

These "receptor" sites were subsequently shown to be localized to

neuronal synaptic regions (Pert et al. 1974) and to overlap anatomically with loci involved in the neural processing of pain (Pert et

al. 1975). The existence of an opiate receptor again suggested the

likelihood of an endogenous compound with opiate properties to

occupy it. Hughes and Kosterlitz (1974) reported the isolation

from neural tissue of a factor (enkephalin) with such properties.

An immense amount of subsequent work has characterised this and

other neural and extraneural compounds with opiate properties

(Adler 1980). Importantly, as with the opiate receptor, the anatomical distribution of endogenous opiate ligands shows overlap

with sites involved in pain processing (Hughes 1975). Table 1

provides a summary of the most critical facts supporting the

existence of an endogenous opiate analgesia system.

The demonstration of a well-defined neural system capable of

potently blocking pain transmission suggests, but by no means

47
proves, that the function of this system is to modulate the

perceived intensity of noxious stimuli. If, in fact, this system

has such a physiological role, then one might expect that the level

of activity within the system would be influenced by impinging

environmental stimuli. If environmental situations could be

identified which produce analgesia, that would give credibility to

the idea that invasive procedures, such as brain stimulation or

narcotic drugs, inhibit pain by mimicking the natural activity

within these pathways.

TABLE 1

Major Anatomical Structures Involved in Analgesia

Manipulation

Neural STIMULATION LESION RECORDING

Area

PAG

BULBAR

RAPHE

DLF

DORSAL

HORN

ELECTRICAL

MORPHINE

CHEMICAL

ELECTRICAL

MORPRINE

OPIATES OTHER

PARTIAL BLOCK

OF MORPHINE

BLOCKS MORPH

BLOCKS SPA?

BLOCKS SPA

AND MORPHINE

ACTIVITY

MORPRINE

SPECIFIC INHIBITION OF

WDR NEURONS

RECEPTORS;

ENKEPHALINS;

PARTIAL NALOX

BLOCK OF SPA;

PARTIAL X-TOL

ENDORPHINS;

NALOX BLOCKS

SPA

RECEPTORS;

ENKEPHALINS

RECEIVES

INPUT

FROM PAG

PROJECTS

FROM BR TO

DORSAL HOE

DIRECT

EFFECTS OF

OPIATES

Summary of available data on analgesia for the major anatomical

structures known to be involved. PAG = periaqueductal gray matter;

DLF = dorsolateral funiculus of the spinal cord; BR = bulbar raphe

which includes nucleus raphe magnus, nucleus reticularis magnocellularis and other associated ventral medullary nuclei; SPA = stimulation produced analgesia; X-Tol = cross tolerance; Nalox = Naloxone;

Morph = Morphine; WBR = Wide Dynamic Range.

48
The first evidence for the environmental activation of an

endogenous opiate analgesia system was provided by Mayer et al.

(1976, 1977). They showed that acupuncture analgesia in humans can

be reversed by the narcotic antagonist naloxone. They suggested

that such a result could be explained if acupuncture produced

analgesia by the release of endogenous opiates.

A systematic search for environmental stimuli which activate pain

inhibitory systems in animals was begun by Hayes et al.

(l976,1978a). They discovered that potent analgesia could be

produced by such diverse stimuli as brief footshock, centrifugal

rotation, and injection of intraperitoneal saline. These effects

appeared to be specific to pain perception in that normal motor

behavior, righting and corneal reflexes, vocalization, startle

responses, and response to touch remain unimpaired (Hayes et al.

1978a). Two important additional concepts emerged from this work.

First was the conclusion that exposure to stress was not sufficient

to produce analgesia. Although all environmental stimuli which

produce analgesia are stressors (Hayes et al. 1978a), the failure of

classical stressors, such as ether vapors and horizontal oscillation, to produce pain inhibition indicated that stress was not the

critical variable responsible (Hayes et al. 1978a). The second

concept resulted from the rather unexpected finding that the opiate

antagonist, naloxone, did not block environmentally induced

analgesias (Hayes et al. 1978a). Therefore, it appeared that

non-opiate systems must exist, in addition to the opiate system

described earlier.

Although the stimuli studied by Hayes et al. (1978a) did not appear

to activate an opiate system , subsequent investigations found clues

that brain endorphins might be involved in at least some types of

environmentally induced analgesias. Akil and coworkers (1976a)

studied the analgesic effects of prolonged footshock. In contrast

to the results of Hayes et al. (1978a), naloxone did partially

antagonize the analgesia. This initial indication of opiate

involvement led Akil and coworkers to look for biochemical evidence

that footshock caused brain opiates to be released. They found

that changes in brain opiate levels did indeed parallel the

development of footshock induced analgesia (FSIA) (Akil et al.

1976a). When tolerance developed to the analgesic effects of

footshock, brain opiate levels returned to control values (Akil et

al. 1976a). In agreement with these results, 3H-leu-enkephalin

binding has been reported to decrease as analgesia increases

(DeVries et al. 1979).

The controversy over the involvement of opiates in footshockinduced analgesia was resolved, in part, by Lewis et al. (1980).

They noted that the duration of footshock used by Hayes et al.

(1978a) and Akil et al. (1976a) differed greatly and wondered

whether this variable might explain the difference in their

results. By comparing the effects of naloxone on analgesia

produced by brief (3 min) vs. prolonged (30 min) footshock, Lewis

et al. (1980) showed that only the latter could be blocked by

naloxone. This suggested that different analgesia systems become

active as the duration of footshock increases.

49
Concurrent with this work of Lewis et al. (1980), we made the

observation that brief shock restricted to the front paws produced

a naloxone-reversible analgesia as measured by the tail flick assay

(Watkins and Mayer 1982). We thought that this was rather puzzling

since Hayes et al. (1978a) and Lewis et al. (1980) found that brief

shock produced non-opiate analgesia. This led us to test whether

naloxone had different effects on analgesia produced by front paw

vs. hind paw shock. We found that naloxone does indeed have

markedly different effects depending upon the body region shocked.

An opiate system appears to be activated by front paw shock since

low doses (0.1 mg/kg) of naloxone antagonize this analgesia. In

contrast, even high doses (20 mg/kg) of naloxone failed to reduce

hind paw shock induced analgesia (Fig. 1). Therefore, a non-opiate

system seems to be-involved in this response.

FIGURE 1

The effect of naloxone (2 i.p. injections of 10 mg/kg) on analgesia

induced by shock delivered to the front paws (FP), hind paws (HP)

or to all four paws (4P). As measured by the tail flick test,

naloxone significantly antagonized front paw FSIA (left) but had no

effect on either hind paw FSIA (center) or four paw FSIA (right).

*=p<0. 05; **p<0.005; ***p<0.001. MPE=Maximal Possible Effect. From

Watkins et al. 1982a. Copyright 1982, Elsevier Biomedical Press.

Reprinted by permission.

Definitive conclusions about opiate involvement in neural systems

are tenuous when based exclusively on the effects of narcotic

antagonists. Narcotic antagonists are known to have effects on

non-opiate systems as well (Hayes et al. 1977; Pert and Walter

1976). Thus, additional lines of evidence are required to infer

opiate involvement. To meet this criterion, we reasoned that if

opiates are involved in front paw footshock-induced analgesia(FSIA),

then front paw FSIA should also be reduced in rats which have been

made tolerant to opiates. To test whether such cross-tolerance

50
exists between morphine analgesia and front paw FSIA, we

continuously infused rats with either morphine or saline for six

days (Watkins et al. 1982a). At this time, the rats given morphine

were tolerant to this opiate since 10 mg/kg morphine no longer

produced analgesia. When the rats were tested for front paw FSIA,

analgesia was greatly reduced in morphine-tolerant rats. Since

front paw FSIA shows cross-tolerance with morphine and is antagonized by naloxone, the involvement of an endogenous opiate system

in this type of analgesia stands on firm ground.

Using this same procedure , rats were tested to see whether crosstolerance could be observed between morphine analgesia and hind paw

FSIA. No cross-tolerance occurred. The fact that hind paw FSIA is

not affected by either high doses of naloxone or morphine tolerance

demonstrates that this manipulation activates an independent

non-opiate analgesia system. Since identical shock parameters were

used in the hind paw FSIA and front paw FSIA experiments, these

results show that factors other than exposure to stress determine

whether non-opiate or opiate systems are activated.

We have studied front paw FSIA and hind paw FSIA in order to define

how these opiate and non-opiate environmental analgesias are

produced. In the following sections, the results of this work will

be presented. The opiate analgesia produced by front paw shock

will be discussed first. As will be seen, several similarities

exist between the opiate analgesias produced by front paw shock and

morphine.

The fact that endogenous opiates are involved in front paw FSIA

does not prove that this effect is mediated by the same circuitry

as morphine analgesia. A critical question was whether front paw

FSIA could be accounted for by release of opiates from the pituitary or sympathetic-adrenal medullary axis since footshock has been

shown to cause opiate release from these sites (Mayer and Watkins

1981). Hypophysectomy failed to reduce front paw FSIA. This shows

that pituitary ß-endorphin is not necessary for front paw FSIA.

Since adrenalectomy and sympathetic blockade actually potentiated

front paw FSIA, our results also clearly show that this analgesia

is not produced by opiates from the sympathetic nervous system.

These data strongly suggest that front paw FSIA, like morphine

analgesia, is effected via opiate pathways within the central

nervous system (Watkins et al. 1982a).

Based on these results, we began to search for the neural pathways

involved in front paw FSIA. We found that front paw FSIA is

abolished by lesions of the dorsolateral funiculus (DLF) of the

spinal cord (Fig. 2). Furthermore, we have shown with brain lesion

studies that, for front paw FSIA as well as morphine analgesia, the

51
FIGURE 2

Effect of bilateral dorsolateral funiculus (DLF) lesions and spinal

transection on front paw FSIA and hind paw FSIA. Left: Bilateral

DLF lesions at either the second thoracic (T2) or third cervical

(C3) vertebral 1evels virtually abolish front paw FSIA. Since DLF

lesions at C3 leave intact all potential intraspinal connections

between the level of stimulus input (front paws) and the lumbosacral cord (controlling the tail flick response), direct intraspinal pathways cannot be involved in this analgesic response.

Pain inhibition must be mediated by supraspinal sites which inhibit

pain via descending pathways within the DLF. Right: Bilateral

DLF lesions at T2 greatly attenuate, but do not abolish, hind paw

FSIA. Immediately after shock termination (0 min), profound analgesia is observed, which then slowly dissipates. No further significant reduction in analgesia is observed following T2 spinalization; spinalized rats remained analgesic through 12 min after hind

paw shock. These results imply that descending pathways involved

in hind paw FSIA only exist within the DLF, and that intraspinal

pathways account for the remaining potent analgesia. MPE=Maximal

Possible Effect. From Watkins and Mayer 1982. Copyright 1982,

The American Association for the Advancement of Science. Reprinted by permission.

descending DLF pathway arises from the nucleus raphe alatus (NRA -

n. raphe magnus and n. reticularis paragigantocellularis) (Fig. 3).

In addition, we have shown that all of the critical circuitry for

this analgesia effect exists below the level of the mesencephalon,

since midcollicular decerebration has no effect on the analgesia

(Watkins and Mayer 1982).

At this point, then, front paw FSIA has been characterized as being

a neural, opiate-mediated phenomenon. Analgesia is produced by

activating brain sites which inhibit pain by way of descending

pathways within the DLF. Yet none of this information pinpoints

where the opiate synapse is located. To determine whether a spinal

cord site of action is involved, intrathecal catheters were implant52
Effect of NRA lesions on front pm FSIA (A) and hind paw FSIA (B).

Compared to controls (open squares), NRA lesions (filled squares)

significantly reduced both front paw FSIA and hind paw FSIA. Since

this lesion reduced front paw FSIA (A) to a degree comparable to

that caused by bilateral DLF lesions (Fig. 2), it appears that the

NRA is the origin of this descending pain inhibitory pathway.

contrast, NRA lesions attenuated, but did not abolish, hind paw

FSIA (B).

ed so that the tips ended at the lumbosacral enlargement. In this

manner, naloxone could be delivered to the spinal cord level

controlling the tail flick reflex which was the behavioral measure

used to assess the pain threshold. Immediately prior to front paw

shock, rats were injected either with saline or 1 μg naloxone.

Spinal naloxone significantly antagonized front paw FSIA (Fig. 4).

This effect is not due to spread of the drug to the brain since the

same dose delivered to high thoracic cord (further from the level

controlling the tail flick reflex yet closer to the brain) failed

to reduce front paw FSIA. These experiments demonstrate that an

opiate synapse critical to the production of front paw FSIA exists

within the spinal cord (Watkins and Mayer 1982).

One intriguing aspect of this naloxone effect is that naloxone can

prevent, but cannot reverse, front paw FSIA (Watkins and Mayer

1982). If this opiate antagonist is injected onto the lumbosacral

spinal cord immediately after the brief (90 sec] shock, analgesia

is -not reduced. Naloxone is effective only if it is delivered

before the induction of analgesia. This implies that brief activation of this system produces a perseverative activity within the

spinal cord which is no longer dependent upon continued opiate

release. These results lead us to speculate that these endogenous

53

429-538 0 - 84 - 5
FIGURE 4

The effect of intrathecal naloxone on front paw and hind paw FSIA.

As measured by the tail flick test, 1 μg of naloxone delivered to

the lumbosacral cord significantly antagonized analgesia induced

by front paw shock (left). In contrast, this same dose of naloxone

failed to attenuate hind paw FSIA (center). The observed antagonism

of front paw FSIA by intrathecal naloxone demonstrates that a critical opioid site exists within the spinal cord. This result cannot

be explained by spread of the antagonist to supraspinal sites since

naloxone delivered to high thoracic cord (right) fails to attenuate

front paw FSIA. *=p<0.05; ***=p<0.005. MPE=Maximal Possible Effect. From Watkins and Mayer. Involvement of spinal opioid systems

in footshock-induced analgesia: Antagonism by naloxone is possible

only before induction of analgesia. Brain Research, 242:309-316,

1982, Copyright 1982, Elsevier Biomedical Press. Reprinted by permission.

spinal opiates may act as neuromodulators of postsynaptic activity,

rather than as classical neurotransmitters.

A parallel series of experiments examined the non-opiate analgesia

produced by hind paw shock. This work indicated that this effect

is also neurally, rather than hormonally, mediated since analgesia

was not reduced by removal of the pituitary or the adrenal glands

(Watkins et al. 1982d). Spinal lesion studies showed that this

effect, like front paw FSIA, is mediated via descending pathways

within the DLF (Watkins et al. 1982c). However, since lesions of

the nucleus raphe alatus failed to abolish hind paw FSIA (Fig. 3),

the neural substrate of this effect is distinct from front paw FSIA

at the level of the medulla (Young et al. 1981). A further difference between the analgesias produced by front paw and hind paw

shock is that hind paw FSIA is only reduced, not abolished, by DLF

lesions. Therefore, it seemed possible that the existence of a

second descending pathway could account for the potent analgesia

54
FIGURE 5

Naloxone reversibility of analgesia classically conditioned to hind

paw shock. Hind paw shock (Day 1) produced profound analgesia, as

measured by the tail flick test (left, open circles). This single

exposure to shock was sufficient to classically condition analgesia,

since placement of the rats on the non-electrified grid on Day 2 was

sufficient to invoke significant analgesia (left, filled circles).

Although hind paw FSIA has previously been demonstrated to be mediated by non-opiate systems, analgesia classically conditioned to

hind paw shock does indeed appear to involve endogenous opioids.

Compared to saline test days (center and right, open squares), both

10 mg/kg systemic (center, filled squares) and 1 μg lumbosacral

(right, filled squares) naloxone significantly antagonized analgesia

classically conditioned to hind paw shock. *=p<0.05; **=p<0.01;

***=p<0.005;  =p<0.001; ** ***=p<0.0005;

Maximal Possible Effect.

******=p<0.0001. MPE=

From Watkins et al. 1982b. Copyright

1982, Elsevier Biomedical Press. Reprinted by permission.

which remained. However, a comparison of hind paw FSIA in

spinalized and DLF lesioned animals indicated that an intraspinal,

rather than descending, pain inhibitory system is responsible for

the analgesia observed following DLF lesions, since spinalization

failed to further reduce the pain inhibitory effects of hind paw

shock (Fig. 2). Thus, segmental circuitry and descending pathways

within the DLF account for the entire analgesic response to hind

paw shock. As with front paw FSIA, the supra-spinal component of

hind paw FSIA is mediated below the level of the mesencephalon,

since it is unaffected by decerebration (Young et al. 1981).

An intriguing aspect of FSIA is that plasticity exists in the

neural circuitry. Using a Pavlovian classical conditioning

paradigm, Hayes et al. (1976) found that rats readily associated

environmental cues with the delivery of shock, such that they

learned to activate their endogenous pain inhibitory systems when

these cues were presented. In this study, the non-electrified

55
shock chamber served as the conditioned stimulus (CS), grid shock

delivered to all four paws served as the unconditioned stimulus

(UCS) and tail flick inhibition served as the unconditioned

response (UCR). Following CS-UCS pairings, exposure to the

non-electrified grid reliably induced analgesia.

Since we have no demonstrated that front paw FSIA is mediated via

a well defined centrifugal opiate pathway, we used brief front paw

shock as the UCS in a classical conditioning paradigm to determine

whether plasticity exists in opiate systems. The following section

summarizes the evidence that animals can learn to activate their

endogenous opiate systems to inhibit pain.

Exposure to the nonelectrified grid (CS) became capable of producing potent analgesia after this CS was paired with front paw

shock (Fig. 5). That this effect is true classical conditioning is

demonstrated by the observations that it shows extinction but cannot be produced by sensitization, backward conditioning, or pseudoconditioning (Watkins et al. 1982b). The fact that we have

observed classically conditioned analgesia to be antagonized by

systemic naloxone (Fig. 5), spinal naloxone (Fig. 5), and morphine

tolerance (Watkins et al. 1982b) strongly suggests that animals

are learning to activate an endogenous opiate system.

Intriguingly, maintenance of the analgesic state again appears to

be independent of continued opiate release.

Like the situation previously discussed for front paw FSIA, we have

observed that naloxone can prevent, but cannot reverse, classically

conditioned analgesia (Watkins et al 1982b).

Although, as described above, opiate (front paw) and non-opiate

(hind paw) FSIA can be differentially elicited, classically

conditioned analgesia appears to always involve opiate pathways

regardless of the body region shocked during conditioning trials.

Classically conditioned analgesia can be antagonized by naloxone

regardless of whether front paw or hind paw shock is used as the

UCS.

The opiate analgesia produced by these classical conditioning

paradigms appears to be neurally, rather than hormonally mediated,

since it is not attenuated by either hypophysectomy or adrenalectomy (Watkins et al. 1982d).

Classical conditioning involves supraspinal circuitry since our

studies have shown that conditioned analgesia is abolished by

bilateral DLF lesions (Watkins et al 1982b). Again, as with front

paw FSIA, nucleus raphe alatus lesions abolish the effect.

However, as might be expected with a higher order behavior,

decerebration abolishes the effect as well (Watkins and Mayer

1982). Finally, the role of the periaqueductal gray matter in the

neural circuitry of endogenous analgesia systems is beginning to

be understood because lesions of this structure reduce the

conditioned effect but not the acute effects of footshock. Fig. 6

provides an overview of the neural circuitry of these systems.

56
FIGURE 6

Summary of the neural circuitry mediating front paw (opiate) FSIA,

hind paw (non-opiate) FSIA and classically conditioned (opiate)

analgesia. Front paw (FP) shock leads to activation of the nucleus

raphe alatus (NRA) within the ventral medulla. This nucleus sends

a descending projection through the dorsolateral funiculus (DLF)

to the dorsal horn of the spinal cord. In turn, endogenous opiates

(EO) are released, resulting in inhibition of pain transmission

neurons (PTN). Hind paw (HP) shock leads to inhibition of pain

transmission neurons via two non-opiate pathways: an intraspinal

pathway and a descending DLF pathway. The latter originates from

the nucleus raphe alatus and from some other yet unidentified medullary area(s). Classically conditioned (opiate) analgesia appears

to result from activation of the same output pathway as front paw

(opiate) FSIA. Following conditioning trials in which the conditioned stimulus (CS) is paired with either front paw shock or hind

paw shock (the unconditioned stimulus), the CS becomes capable of

activating rostral centers in the brain. In turn, this leads to

activation of the periaqueductal gray (PAG) and subsequently to

activation of the nucleus raphe alatus. This results, via a descending DLF pathway, in release of endogenous opiates within the

dorsal horn, producing analgesia. From Watkins and Mayer 1982.

Copyright 1982, The American Association for the Advancement of

Science. Reprinted by permission.

In another series of experiments we have begun to examine the

neurochemical bases of pain modulation. One approach was motivated

by the observation that cholecystokinin (CCK) has effects opposite

those of opiates on a number of behaviors. We have made a number of

striking observations about CCK and analgesia: (1) CCK (5 μg/kg,

i.p.) greatly reduces analgesia produced by 10 mg/kg morphine (Fig.

7) (Faris et al. 1983). (2) CCK (as little as 1.5 μg/kg, i.p.)

reduces environmentally produced opiate analgesias (front paw FSIA,

57
shock chamber served as the conditioned stimulus (CS), grid shock

delivered to all four paws served as the unconditioned stimulus

(UCS) and tail flick inhibition served as the unconditioned

response (UCR). Following CS-UCS pairings, exposure to the

non-electrified grid reliably induced analgesia.

Since we have now demonstrated that front paw FSIA is mediated via

a well defined centrifugal opiate pathway, we used brief front paw

shock as the UCS in a classical conditioning paradigm to determine

whether plasticity exists in opiate systems. The following section

summarizes the evidence that animals can learn to activate their

endogenous opiate systems to inhibit pain.

Exposure to the nonelectrified grid (CS) became capable of producing potent analgesia after this CS was paired with front paw

shock (Fig. 5). That this effect is true classical conditioning is

demonstrated by the observations that it shows extinction but cannot be produced by sensitization, backward conditioning, or pseudoconditioning (Watkins et al. 1982b). The fact that we have

observed classically conditioned analgesia to be antagonized by

systemic naloxone (Fig. 5), spinal naloxone (Fig. 5), and morphine

tolerance (Watkins et al. 1982b) strongly suggests that animals

are learning to activate an endogenous opiate system.

Intriguingly, maintenance of the analgesic state again appears to

be independent of continued opiate release.

Like the situation previously discussed for front paw FSIA, we have

observed that naloxone can prevent, but cannot reverse, classically

conditioned analgesia (Watkins et al 1982b).

Although, as described above, opiate (front paw) and non-opiate

(hind paw) FSIA can be differentially elicited, classically

conditioned analgesia appears to always involve opiate pathways

regardless of the body region shocked during conditioning trials.

Classically conditioned analgesia can be antagonized by naloxone

regardless of whether front paw or hind paw shock is used as the

ucs .

The opiate analgesia produced by these classical conditioning

paradigms appears to be neurally, rather than hormonally mediated,

since it is not attenuated by either hypophysectomy or adrenalectomy (Watkins et al. 1982d).

Classical conditioning involves supraspinal circuitry since our

studies have shown that conditioned analgesia is abolished by

bilateral DLF lesions (Watkins et al 1982b). Again, as with front

paw FSIA, nucleus raphe alatus lesions abolish the effect.

However, as might be expected with a higher order behavior,

decerebration abolishes the effect as well (Watkins and Mayer

1982). Finally, the role of the periaqueductal gray matter in the

neural circuitry of endogenous analgesia systems is beginning to

be understood because lesions of this structure reduce the

conditioned effect but not the acute effects of footshock. Fig. 6

provides an overview of the neural circuitry of these systems.

56
experiments examining the role of spinal monoamines in various

analgesia systems.

In one series of experiments, the effects of spinal cord serotonin

depletion or combined serotonin and norepinephrine depletion on

analgesia elicited by electrical stimulation of, or morphine

microinjection into, the periaqueductal gray were tested

(Johannessen et al 1982). Spinal cord serotonin was depleted by

intrathecal injection of 5,7-dihydroxytryptamine (5,7-DHT),

preceded by systemic desipramine, while 5,7-DHT alone was used to

deplete both norepinephrine and serotonin. Selective serotonin

depletion had no effect on analgesia induced by either method at 24

hrs, one week, or two weeks after treatment. Depletion of both

monoamines had no effect on stimulation-produced analgesia 24 hrs

and one week after treatment, but produced a slight attenuation two

and three weeks after treatment. In contrast, depletion of both

monoamines drastically attenuated morphine analgesia 24 hrs after

treatment. Thus, although total c.n.s. depletion of serotonin can

reduce both stimulation-produced analgesia and morphine analgesia,

medullospinal serotonin systems do not appear to be involved.

Although this lack of involvement of medullospinal serotonin

systems may at first glance appear perplexing, a series of

anatomical studies we have done makes this result more coherent. A

critical fact concerning the organization of supraspinal neural

systems which control pain is that the output pathway from the

brain appears to descend to the spinal cord by way of the dorsal

lateral funiculus (DLF). DLF lesions greatly reduce or abolish

analgesia produced by brain stimulation, systemic morphine, and

morphine microinjection (Mayer 1980). Thus, we felt it was of

particular importance to describe carefully the origins of this

pathway before undertaking behavioral and neurophysiological

studies of brain centers involved in analgesia. Several studies

utilizing a new horseradish peroxidase gel technique developed in

our laboratory (Griffin et al. 1979) have examined the problem. We

have shown that the population of neurons in the medullary raphe

region contributing to the DLF consists of cells in nucleus raphe

magnus (NRM) and reticularis magnocellularis (Rmc) and roughly

corresponds to the serotonergic cell group B3. We have named this

region the nucleus raphe alatus (NRA), and this work has redefined

the anatomical organization of the medullary raphe nuclei which

contribute to the DLF (Watkins et al. 1980). The medullary nucleus

raphe alatus, which gives rise to fibers which descend in the DLF,

is a sensitive site for the production of analgesia by electrical

and pharmacological methods (Mayer 1980). Indirect evidence

suggests that descending serotonergic fibers from area B3 may play

a role in descending inhibition. The cells of B3 show a similar

distribution to those of NRA, however, there is no direct evidence

that serotonergic fibers from B3 descend in the DLF.

In order to examine this question, we performed a study in which

the cell bodies of NRA were labelled retrogradely with HRP by

implanting a small piece of HRP-gel unilaterally into the cervical

59
DLF. Two days later, the method of Bowker et al. (1981) was used

to simultaneously visualize both retrogradely labelled cells and

cells exhibiting serotonin-like immunoreactivity (SLI). Extremely

few double-labelled cells were seen (Johannessen et al. 1981).

Retrogradely labelled cells of NRA exhibited a different distribution than SLI cells. The SLI cells of B3 lie ventral to NRA (Fig.

8). Some intermingling of retrogradely labelled cells and SLI

FIGURE 8

Composite of cells retrogradely labelled from the right dorsolateral

funiculus (DLF) (stars) and cells exhibiting serotonin-like immunoreactivity (filled circles) at the level of the n. raphe magnus.

No double labelled cells were seen in this section. Note intermingling of DLF projecting cells and serotonin cells near the midline.

cells was seen, especially near the midline. At the level of the

facial nucleus, 25 retrogradely labelled cells and 55 SLI cells

were seen in a typical hemisection, while no more than two doublelabelled cells could be identified. These results suggest that

serotonin is not a major component of the DLF projection which

originates in the NRA. This is consistent with evidence indicating

that a descending serotonergic projection is unnecessary to elicit

some types of analgesia.

A study examining the effects of these same monoamine manipulations

on footshock induced analgesia has been conducted. Interestingly,

while hind paw FSIA is unaffected by monoamine depletions, front

paw FSIA is reduced by selective spinal cord serotonin depletion

(Fig. 9). This study has complex but important implications.

Since (1) the DLF is necessary for front paw FSIA, (2) the n. raphe

alatus is necessary for front paw FSIA, and (3) serotonergic output

60
from NRA does not descend via the DLF, these results indicate that

a synergism of serotonergic and non-serotonergic descending

pathways may sometimes be necessary to produce analgesia.

FIGURE 9

Effect of spinal cord serotonin depletion (5HT) or combined serotonin and norepinephrine depletion (5HT & NE) on front paw FSIA.

Compared to controls (open circles), both 5HT (closed circles) and

5HT & NE (open squares) depletion reliably reduced analgesia induced

by brief front paw shock. Since intrathecal BC 105 (5HT antagonist)

and intrathecal phentolantine (NE antagonist) also reduce front paw

FSIA, NE and 5HT appear to be involved in the production of this

analgesia at the level of the spinal cord. MPE=Maximal Possible

Effect.

These studies of front paw FSIA, hind paw FSIA, and classically

conditioned analgesia provide strong support for the existence of

multiple endogenous pain modulatory systems within the central

nervous system. At least three systems have been identified (Fig.

7). The first two pathways mediate the neural non-opiate analgesia

61
observed following hind paw shock. These consist of an intraspinal

pathway and a descending DLP pathway with supraspinal origin. The

third is a neural opiate analgesia which is produced by front paw

shock or by classical conditioning using front paw or hind paw

shock as the UCS. This opiate analgesia is effected solely via

descending pathways within the spinal cord. Thus, front paw FSIA

and classically conditioned analgesia provide the first unequivocal

demonstrations of neural opiate pathways activated in response to

environmental stimuli.

However, a review of the literature indicates that even these three

systems do not account for all of the pain inhibitory responses

which have been reported. As summarized in Table 2, presently

available evidence indicates that four classes of analgesia exist:

neural/opiate, hormonal/opiate, neural/non-opiate, and hormonal/nonopiate. The criteria used to classify analgesia as opiate include

naloxone reversibility and cross-tolerance to morphine. Hormonal

analgesia is characterized as being attenuated either by

adrenalectomy, adrenal demedullation, or hypophysectomy. These

latter criteria were chosen since all environmental stimuli which

produce analgesia activate the pituitary-adrenal cortical and

sympathetic-adrenal medullary axes. Brain stimulation is listed in

two classes, neural/opiate and neural/non-opiate since it can

apparently activate both opiate and non-opiate pain inhibitory

pathways. Regarding the neural substrates of these various

analgesic responses, the most comprehensive data are available on

the effect of dorsolateral funiculus (DLF) lesions, nucleus raphe

alatus (n. r. alatus) lesions and periaqueductal gray (PAG)

lesions. As can be seen, DLF lesions attenuate all analgesic

manipulations which have been tested, suggesting that the DLF may

form the final common pathway for endogenous pain inhibitory

systems. (Akil et al. 1976a; Mayer 1980; Mayer and Price 1976.)

At this point, I would like to make some parallels between our work

in rats and experimental and clinical studies in humans. This will

be done in order to highlight the potential relevance of this work

to the very difficult problem of treating pain syndromes in man.

Throughout this discussion, it will be important to bear in mind

that a number of distinct modulatory systems have been identified

under controlled laboratory conditions. In the more naturalistic

circumstances of clinical research, it is likely that more than one

of these systems may be active at any given time, which may account

for the variability and controversy in the clinical literature.

There are at least two situations available for study in which

endogenous pain modulatory systems may be active in man. The first

involves the basal, tonic activity within these systems and allows

the experimenter to assess whether pain inhibition occurs continuous ly , at least to some degree. The second involves clinical

manipulations which attempt to activate pain inhibitory systems.

Attempts have been made to determine whether pain modulatory

systems are tonically active. The assumption made by these studies

62
TABLE 2

Summary of Currently Available Data on Endogenous Analgesia

Systems

 = potentiation, = attenuation, 0 = no effect, ? =

conflicting data exist indicating either no effect or

attenuation, blank = no data are available, • = inappropriate category.

63
has been that administration of opiate antagonists should alter the

perception of pain if opiate systems are tonically active. This

change in pain perception would be recorded either as a decreased

pain threshold or an increased level of ongoing pain. In general,

however, naloxone has failed to affect pain thresholds of normal

human volunteers (El-Sobky et al. 1976; Grevert and Goldstein 1978;

Mayer et al. 1977). In contrast to these negative results,

Buchsbaum et al. (1977) found that naloxone lowered the thresholds

on subjects with naturally high pain thresholds, yet had no effect

in subjects with low pain thresholds.

Naloxone appears to be more consistently effective when delivered

to experimental subjects who are experiencing some level of

clinical pain. Therefore, circumstances have been observed in

which spontaneous activity of an endogenous opiate analgesia system

occurs. Importantly, ongoing pain is one factor that appears to

activate this system. In this regard, these results are consistent

with the animal studies described above in which pain was observed

to be a powerful activator of endogenous analgesia systems.

A number of manipulations are known to have some degree of clinical

efficacy for the reduction of pain. Most of these procedures were

developed before the recent explosion of information about endogenous pain control systems. Indeed, many of them evolved from

theoretical approaches which are now outdated or incorrect.

Nevertheless, the procedures are efficacious. It may be informative to re-examine them in the light of current knowledge.

The belief that an acute painful stimulus can be used to alleviate

ongoing pain has been held since antiquity and is known as counterirritation. This procedure has a great deal in common with

acupuncture and TNS. All use the application of somatic stimuli,

either noxious or innocuous, to obtain relief from pain. Importantly, pain relief persists beyond the period of treatment in all

cases. The site of treatment in relation to the painful area is

highly variable, ranging from the painful dermatome, itself, to a

theoretically unpredictable constellation of points in classical

Chinese acupuncture. Lastly, the duration of treatment varies from

less than a minute to hours. All of these factors, as we have

seen, are important determinants of the effects produced by

footshock in animals. Thus, the highly variable effects observed

in the clinic would be predicted from animal research.

Nevertheless, human data suggest the involvement of the same

systems described above.

The involvement of an opiate system in these types of analgesia was

first suggested by Layer et al. (1977) who showed that the

increased pain thresholds produced by traditional acupuncture in

man could be completely reversed by naloxone. Other investigators

(Chapman and Benedetti 1977) found that naloxone only partially

reduced electroacupuncture analgesia. The differences in the

magnitude of the effects seen in these studies is particularly

enlightening considering the animal studies described above. Mayer

et al (1977) used the ho-ku points in the hands to induce analgesia

in the teeth, an acupuncture point far removed from the painful

region. In contrast, Chapman and Benedetti (1977) stimulated the

64
face to produce analgesia in the teeth and saw only a very small

effect of naloxone. Thus, it seems likely that, as in animal

experiments, stimulation of regions adjacent to the painful area

activate non-opiate analgesia systems, whereas stimulation of

distant dermatomes activates opiate systems.

Other parameters of stimulation also appear to be critical in

determining whether opiate or non-opiate systems are involved.

Sjolund and Eriksson (1979) have recently shown that high

frequency/low intensity and low frequency/high intensity nerve

stimulation can both alleviate clinical pain. However, only the

analgesia produced by low frequency/high intensity stimulation

could be reversed by naloxone. From this work, it appears that

noxious stimulation is required for the activation of opiate

inhibitory systems. In fact, that acupuncture and TNS should be

painful to produce maximal effects has been pointed out by several

workers (Fox and Melzack 1975; Mann 1974; Melzack 1976).

In-conclusion, acupuncture and TNS appear to be forms of counterirritation which activate both opiate and non-opiate systems. The

variable clinical outcomes observed following these treatments

probably result from differential recruitment of segmental,

extrasegmental, opiate and non-opiate pain inhibitory systems, all

of which are now known to be activated by these types of

stimulation in animals.

Naloxone has also been used to examine whether endogenous opiates

are involved in placebo analgesia. Levine and coworkers (1978a and

b) reported that naloxone antagonized placebo effects. Although

this conclusion has been questioned on technical grounds (Karczyn

1978) , no conflicting data have been published, and the possibility

that opiates are involved in some aspect of placebo analgesia

appears particularly reasonable considering the fact that footshock

analgesia can be classically conditioned in rats. Placebo

analgesia can easily be conceived of as a classical conditioning

paradigm wherein the placebo manipulation (i.e., injections, pills)

serves as the conditioned stimulus and prior medication or

treatment serves as the unconditioned stimulus.

Although explanations of this sort are clearly speculative, they

are indicative of the wealth of concepts from experimental pain

research now available for clinical evaluation. Our increasing

knowledge of pain modulatory systems has the potential not only of

providing explanations of current therapies but of suggesting new

approaches for the control of pain. The preponderance of current

pain therapies involve either the surgical destruction of neural

tissue or the use of addictive drugs. Such procedures offer great

difficulties for the prolonged treatment of chronic pain. If

multiple pain inhibitory systems could be activated pharmacologically or otherwise in an alternating sequence, the problems of

tissue destruction and addiction could be circumvented.

A primary conclusion of the present research as well as much other

research in this area is that there are numerous "analgesia

systems" (Watkins and Mayer 1982; Lewis et al. 1980). The concept

65
of an "analgesia system," however may be more an artifact of our

desire to control pain than a true reflection of the evolutionary

development and normal functioning of the nervous system. That the

nervous system evolved even one, much less numerous "analgesia

systems" is contradicted by several observations: (1) Many of

these systems seem to be activated by only the most extreme of

naturally occurring conditions such as intense pain or stress.

Under such conditions in nature, animals would be unlikely to

survive. (2) The major somatosensory pathology is the presence of

pain without apparent cause, not its absence. If all of this

circuitry existed to produce analgesia, one would expect the

opposite.

Although some or all of these systems may exist for the specific

purpose of modulating the flow to consciousness of information

about tissue damage, we feel it may be more heuristic to examine

such circuitry in the broader context of somatosensory processing.

It should be understood that the evaluation of tissue damage versus

other somatic inputs presents a distinct dilemma to the nervous

system. The nervous system must be designed to evaluate and escape

from tissue damaging stimuli as rapidly as possible. Yet, physical

contact with the somatic environment is obviously useful to the

organism in numerous realms. Thus it seems likely that complex

neural systems would evolve to mitigate this conflict between

somatic-informational systems and somatic avoidance (pain) systems.

Viewing somatosensory systems in this light has no less profound

implications for the practical applications to pain treatment and

may provide a more comprehensive understanding of sensory

processing.

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ACKNOWLEDGMENT

This work was supported in part by Grant No. DAOOO576 from the

National Institute on Drug Abuse.

AUTHOR

David J. Mayer, Ph.D.

Department of Physiology and Biophysics

Medical College of Virginia

Virginia Commonwealth University

Richmond, Virginia 23298

69
Mechanisms of Pain and Analgesia

as Revealed by Opiate Research:

Summary and Recommendations

Roger M. Brown, Ph.D., and

Theodore M. Pinkert, M.D., J.D.

Historically, the National Institute on Drug Abuse (NIDA) and its

predecessors in the Public Health Service have been deeply committed

to research in the area of analgesic drugs and analgesia. This

commitment has extended through the years to become an elemental

part of almost all of NIDA's programs, from basic research to

treatment and services research to the public dissemination of those

research findings through publications and professional meetings.

This Research Analysis and Utilization Systems (RAUS) review is a

part of a continuing process of evaluation of current research

findings in this area, and an attempt to discern the most promising

areas of study for the future investment of effort.

The search for a remedy from acute and chronic pain is centuries

old. Only recently, however, has the phenomenon of pain and

analgesia been subjected to rigorous experimentation and systematic

study. The observation of the remarkable analgesic properties of

the opiate drugs revolutionized the treatment of pain from an

empirical point of view. Unfortunately, opiates were soon

recognized as also possessing the liability of producing euphoria,

tolerance, and physical dependence. These properties of the

then-known analgesic drugs led to drug dependence among the

afflicted, even when the source of pain could be successfully

treated. This led to a search which continues today for new

pharmacological entities which possess the analgesic properties of

the classic drugs in this field, while diminishing the risks of drug

dependence or abuse. A corresponding scientific inquiry into the

physiology, anatomy, biochemistry, and psychology of pain began at a

later point in time. and has proceeded much more slowly, only

gradually beginning to reveal the secrets of nociception in research

conducted over the last two decades.

It should not have been surprising that one of the major outgrowths

of drug abuse research has been the elucidation of nociceptive and

antinociceptive mechanisms and the micro-architecture of pain in the

neural substrate. Mood changes, the development of tolerance to

increasing doses, and physical dependence are shared properties of

many drugs of abuse and of most of the drugs which are effective in

70
pain relief. Therefore, progress in understanding addictive

processes is inextricably tied to (and inseparable from) advances in

research in pain and analgesia.

A direct result of NIDA-funded opiate research over the past 10

years has been the discovery of endogenous systems of pain

modulation and control. The neuroanatomy of pain pathways is no

longer restricted to discussion of main afferent "trunk" lines

coursing UP the spinal cord, but now additionally focuses on

discrete microanatomical locations designated as opiate receptors.

At these locations, previously unknown endogenous compounds

(endorphins, enkephalins, and other peptides) have been shown by

ingeniously designed experimentation to be intimately involved in

the modulation of pain perception. Functional investigations have

demonstrated localized sites of pain modulation in both the brain

and spinal cord. In addition to the opioid systems, studies in

non-primate species have revealed the presence of non-opiate

modulated pain pathways the significance of which is not yet

apparent for man. Clinical studies of both the classical opiate

compounds and the new synthetic opioid and non-opioid analgesics

have established their relative potencies, frequency and type of

side effects, and pharmacokinetic/pharmacodynamic models which help

to explain some of the idiosyncratic properties associated with a

particular drug or drug family. Other clinical investigations have

systematically explored non-chemotherapeutic approaches to pain,

including such widely disparate modalities as acupuncture, behavior

modification, and psychotherapy.

OVERVIEW

Dr. Fields presents an anatomical picture of the pain suppression

systems as they are currently understood, and points to the

neuroanatomical overlap between pain modulation and opiate action.

The endoqenous opioid systems which are closely associated with pain

modulation occur at the level of the diencephalon, midbrain,

medulla, and soinal cord. Two important loci at which analgesics

act are presented and discussed. First, they act within the spinal

cord to block impulse transmission through the dorsal horn.

Secondly, they act within the brain itself to alter the perception

of and resoonse to painful stimuli. The cellular, ultrastructural

behavioral, and clinical neurophysiological strategies which have

been applied to test this concept of pain modulation are presented

in this chapter to develop the current model of pain suppression

systems.

Dr. Gebhart reviews the neuropharmacology and neurochemistry of

nociception/antinociception. In addition to peptidergic systems,

other neurotransmitter/neuromodulator systems are important in

mediating pain pathways, and these include serotonin, norepineph-

. .

rine, and gamma-aminobutyric acid, among others. Dr. Gebhart points

out the importance of behavioral correlates to either neuropharmacological or neurophysiological measures of analgesia so that

earlier contradictions in the literature can be clarified, and so

that multiple mechanisms involved in pain suppression and inhibition

can be resolved.

71
Dr Houde (who was unable to prepare a written report for this

monograph) reviewed the clinical study of opiate and non-opiate

analgesics. His work has systematized the study of the analgesic

effectiveness of a broad variety of classical analgesic compounds

and provided a scientific basis for the selection of an analgesic

regimen which may limit or postpone the development of tolerance and

dependence in pain patients. In addition, Dr. Houde's studies

comparing the analgesic effectiveness of equianalgesic doses of

morphine and heroin have put to rest some of the popular

misconceptions of the superiority of heroin over other analgesic

drugs.

Dr. O'Brien and Dr. Weisbrot discuss pain treatment and review

current methods which include behavior modification, classical

conditioning, biofeedback, hypnosis, and psychotherapy. The

difficulty with pharmacotherapy is discussed, and there is emphasis

throughout the chapter on the importance of research in evaluating

treatment efficacy and outcome.

Finally, environmental influences are well known to influence pain

processing. For example, chronic pain is influenced by acute pain.

Dr. Mayer reviews behavioral evidence for the existence of multiple

pain suppression systems ---both opioid and non-opioid in nature. A

functional analysis of analgesic mechanisms indicates important

differences in the physiological responses to noxious stimuli that

are aversive in their own right, as opposed to those stimuli which

have become aversive through learning. These differences are

important because, unlike the acute pain patient, the chronic pain

patient-can potentially develop extensive amounts of learned pain

behavior.

NEW DIRECTIONS

The members of the review panel were asked to present their ideas

for future research which would build upon our current knowledge

base. Most of the question and answer sessions following the oral

presentation of each paper as well as most of the discussion session

at the end of the meeting centered on this issue. The following is

a distillation of the highlights of some of their recommendations,

which is not intended as, and should not be considered to be, an

exhaustive list.

Recognizing that not all drugs are abused, there needs to be a

search for those shared or unifying factors that abused substances

have in common. One essential step is an enhanced understanding of

the underlying neural mechanisms of drug-seeking behavior. This

would provide a window for understanding how certain special

characteristics of all abused substances create, or are a cause for,

their being abused.

In addition to further exploration of the microanatomical

neurocircuitry and the neurochemistry involved in opiate analgesia,

the search for normal physiological pain suppression systems needs

to be expanded. This would include characterization of the activity

72
occurring at non-opiate synapses after stimulation; the development

of immunocytochemical methods for the study of putative non-opioid

pain suppression systems; and further studies of the functional

meaning of concentrations of particular types of opiate receptors.

and their chemical transmitters at different locations within the

nervous system which may operate in concert with non-opioid pain

modulation.

The search must be continued for neurotransmitter substances which

are as yet undiscovered, as well as a more complete characterization

of the effects of those which are known. What are the changes in

the neuronal cell membranes caused by transmitter activity? What is

their effect on conductance? What are the events leading to

termination of the action of opioid peptides in the brain (via

"enkephalinase-like" activity?), and what are the implications of

derangements in this system for the development of tolerance? Do

peptide fragments from opioid precursors have biological and

practical functions? Do differences in central nervous system (CNS)

opioid metabolism explain why certain individuals become (or remain)

drug abusers?

There is a great deal more that must be learned about the activities

of neurotransmitters and the sites at which they are active. What

is their anatomical distribution, and what is the functional effect

of that distribution? Are the actions of a particular neurotransmitter characteristic (e.g., GABA is generally inhibitory), or does

the result of a transmitter action depend on how a neuroreceptor

site is activated, or its location within ascending or descending

pathways?

Another issue requiring further study is an examination of the true

nature of "high-affinity" vs. "low affinity" opiate binding sites.

Is it a subtle change in the tertiary structure of the receptor that

is responsible for an alteration in subsesuent binding, or are the

receptors "anatomically" different, but located in functionally

similar locations? Another unresolved issue is the "true"

anatomical relationship between opiate receptor sites, i.e., a

determination as to whether the identified receptors are distinctly

set apart or just different parts of one large receptor complex.

There is a need to develop better animal models for the study of

chronic pain. Studies conducted to date have been based primarily

on time-limited noxious events which do not have the capacity for

demonstrating the neuroanatomical and neurochemical consequences of

chronic exposure to pain, or chronic administration of analgesics.

This gap in our knowledge is paralleled in clinical studies, in

which there exists the need for further evaluations of analgesic

drugs after they have achieved steady-state levels.

More time and effort will also be required to understand the

pharmacodynamic/pharmacokinetic properties of a large group of

analgesic drugs which have not been studied using these methods.

The effects of opioids and other drugs on patients with previous

narcotic exposure needs to be elucidated in well-controlled studies,

as well as the related issue of measuring interindividual variations

7 3
in the general clinical response to analgesic drugs. Previous

studies have shown statistically significant differences in

analgesic drug responses that have been related to age, sex, race,

etc., but there may be other important intrinsic factors that remain

to be sorted out.

New opioid and non-opioid analgesic drugs are continually being

developed (including drugs of the mixed agonist/antagonist type),

and these must be studied for their capacity to produce tolerance

and dependence before they can be safely released for general use.

An unexpected bonus that might be derived from such studies would be

the discovery that one or more of these drugs potentiate an opiate's

analgesic action without potentiating the development of tolerance.

This would have important implications for the treatment of chronic

pain, as well as for an understanding of the mechanism(s) of drug

tolerance itself.

There is also a need for further research to develop a better

taxonomy of pain. An improved classification of pain, and pain

syndromes, would lead to a better understanding of the natural

history, prognosis, and most efficacious treatment for particular

pain syndromes. If this led to an improvement in the care received

by pain patients, we would undoubtedly prevent a significant amount

of drug abuse and misuse caused by the inadequate or inappropriate

treatment of chronic pain patients.

CONCLUSIONS

NIDA'S support of opiate research was a natural outgrowth of its

concern with the rising tide in the abuse of these substances in the

late '60s and early '70s. The discovery of a complex internal

system which was stimulated by, and then subsequently modulated by,

the organism's own responses to both exogenous stimuli and analgesic

drug administration was to have important implications for the study

of drug abuse per se, and to drastically change our understanding of

pain and analgesia. The concept of a specific receptor (or

receptors) which is activated to produce characteristic organismic

responses for particular drugs is opening new research frames of

reference for the study of non-opiate drugs of abuse. Some of the

methodologies developed for the study of pain and analgesia have

become imoortant for the study and measurement of other drugs of

abuse, for the understanding of antagonist groups of drugs, and for

reducing the potential of developing drug dependence inadvertently

in the treatment of pain patients.

Research that adds to our understanding of the physiological,

behavioral, and psychological mechanisms of opiate abuse will

continue to have important implications for the study of pain and

analgesia and vice versa. Clearly, this cross-fertilization between

two closely related species of research has borne abundant fruit.

It is important that NIDA maintain its vigorous support of research

in this field to ensure continued advances.

74
AUTHORS

Roger M. Brown, Ph.D.

Neurosciences Research Branch

Division of Preclinical Research

National Institute on Drug Abuse

Rockville, Maryland 20857

Theodore M. Pinkert, M.D.,J.D.

Clinical and Behavioral Pharmacology Branch

Division of Clinical Research

National Institute on Drug Abuse

Rockville, Maryland 20857

75
monograph series

While limited supplies last, single copies of the monographs may

be obtained free of charge from the National Clearinghouse for

Drug Abuse Information (NCDAI). Please contact NCDAI also for

information about availability of coming issues and other

publications of the National Institute on Drug Abuse relevant to

drug abuse research.

Additional copies may be purchased from the U.S. Government

Printing Office (GPO) and/or the National Technical Information

Service (NTIS) as indicated. NTIS prices are for paper copy.

Microfiche copies, at $4.50, are also available from NTIS.

Prices from either source are subject to change.

Addresses are:

NCDAI

National Clearinghouse for Drug Abuse Information

Room 1OA5600 Fishers Lane

Rockville, Maryland 20857

GPO NTIS

Superintendent of Documents National Technical Information

U.S. Government Printing Office Service

Washington, D.C. 20402 U.S. Department of Commerce

Springfield, Virginia 22161

1 FINDINGS OF DRUG ABUSE RESEARCH. Not available from NCDAI.

Vol. 1: GPO out of stock NTIS PB #272 867/AS $32.50

Vol. 2: GPO out of stock NTIS PB #272 868/AS $29.50

2 OPERATIONAL DEFINITIONS IN SOCIO-BEHAVIORAL DRUG USE RESEARCH

1975. Jack Elinson, Ph.D., and David Nurco, Ph.D., eds. Not

available from NCDAI.

GPO out of stock NTIS PB #246 338/AS $16

3 AMINERGIC HYPOTHESES OF BEHAVIOR: REALITY OR CLICHE? Bruce J.

Bernard, Ph.D., ed.

GPO Stock #017-024-00486-3 $6.50 NTIS PB #246 687/AS $16

76
4 NARCOTIC ANTAGONISTS: THE SEARCH FOR LONG-ACTING PREPARATIONS.

Robert Willette, Ph.D., ed.

GPO out of stock NTIS PB #247 096/AS $8.50

5 YOUNG MEN AND DRUGS: A NATIONWIDE'SURVEY. John A. O'Donnell,

Ph.D., et al.

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6 EFFECTS OF LABELING THE "DRUG ABUSER": AN INQUIRY. Jay R.

Williams, Ph.D.

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7 CANNABINOID ASSAYS IN HUMANS. Robert Willette, Ph.D., ed.

GPO Stock #017-024-00510-O $6.00 NTIS PB #251 905/AS $14.50

8 Rx: 3x/WEEK LAAM - ALTERNATIVE TO METHADONE. Jack Blaine, M.D.,

and Pierre Renault, M.D., eds.

Not available from GPO NTIS PB #253 763/AS $14.50

9 NARCOTIC ANTAGONISTS: NALTREXONE PROGRESS REPORT. Demetrios

Julius, M.D., and Pierre Renault, M.D., eds.

GPO Stock #017-024-00521-5 $7.00 NTIS PB #255 833/AS $17.50

10 EPIDEMIOLOGY OF DRUG ABUSE: CURRENT ISSUES. Louise G. Richards,

Ph.D., and Louise B. Blevens, eds.

GPO Stock #017-024-00571-1 $6.50 NTIS PB #266 691/AS $22

11 DRUGS AND DRIVING. Robert Willette, Ph.D., ed. Reviews

research on effects of drugs on psychomotor performance, focusing

on measures of impairment by different drugs at various levels.

GPO Stock #017-024-00576-2 $5.50 NTIS PB #269 602/AS $16

12 PSYCHODYNAMICS OF DRUG DEPENDENCE. Jack D. Blaine, M.D., and

Demetrios A. Julius, M.D., eds. Theoretical and clinical papers

concerned with the intrapsychic determinants of drug addiction.

GPO Stock #017-024-00642-4 $5.50 NTIS PB #276 084/AS $17.50

13 COCAINE: 1977. Robert C. Petersen, Ph.D., and Richard C.

Stillman, M.D., eds. Reports the extent and limits of current

knowledge about cocaine, its use and misuse.

GPO Stock #017-024-00592-4 $6.00 NTIS PB #269 175/AS $19

14 MARIHUANA RESEARCH FINDINGS: 1976. Robert C. Petersen, Ph.D.,

ed. Technical papers on which the 6th Marihuana and Health report

to Congress was based.

GPO out of stock NTIS PB #271 279/AS $22

15 REVIEW OF INHALANTS: EUPHORIA TO DYSFUNCTION. Charles Wm.

Sharp, Ph.D., and Mary Lee Brehm, Ph.D., eds. Review of inhalant

abuse, including an extensive bibliography.

GPO Stock #017-024-00650-5 $7.50 NTIS PB #275 798/AS $28

77
16 THE EPIDEMIOLOGY OF HEROIN AND OTHER NARCOTICS. Joan Dunne

Rittenhouse, Ph.D., ed. Task Force report on research

technologies and implications for studying heroin-narcotic use.

GPO Stock #017-024-00690-4 $6.50 NTIS PB #276 357/AS $20.50

17 RESEARCH ON SMOKING BEHAVIOR. Murray E. Jarvik, M.D., Ph.D.,

et al., eds. Includes epidemiology, etiology, consequences of

use, and approaches to behavioral change. From a NIDA-supported

UCLA conference.

GPO Stock #017-024-00694-7 $7.50 NTIS PB #276 353/AS $29.50

18 BEHAVIORAL TOLERANCE: RESEARCH AND TREATMENT IMPLICATIONS.

Norman A. Krasnegor, Ph.D., ed. Theoretical and empirical studies

of nonpharmacologic factors in development of drug tolerance.

GPO Stock #017-024-00699-8 $5.50 NTIS PB #276 337/AS $16

19 THE INTERNATIONAL CHALLENGE OF DRUG ABUSE. Robert C. Petersen,

Ph.D., ed. Papers from the VI World Congress of Psychiatry.

GPO Stock #017-024-00822-2 $7.50 NTIS PB #293 807/AS $28

20 SELF-ADMINISTRATION OF ABUSED SUBSTANCES: METHODS FOR STUDY.

Norman A. Krasnegor, Ph.D., ed. Techniques used to study basic

processes underlying abuse of drugs, ethanol, food, and tobacco.

GPO Stock #017-024-00794-3 $6.50 NTIS PB #288 471/AS $22

21 PHENCYCLIDINE (PCP) ABUSE: AN APPRAISAL. Robert C. Petersen,

Ph.D., and Richard C. Stillman, M.D., eds. For clinicians and

researchers, assessing the problem of PCP abuse.

GPO Stock #017-024-00785-4 $7.00 NTIS PB #288 472/AS $25

22 QUASAR: QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS OF

ANALGESICS, NARCOTIC ANTAGONISTS, AND HALLUCINOGENS. Gene

Barnett, Ph.D.; Milan Trsic, Ph.D.; and Robert Willette, Ph.D.;

eds. Reports from an interdisciplinary conference on molecular

drug-receptor interactions.

GPO Stock #017-024-00786-2 $8.00 NTIS PB #292 265/AS $35.50

23 CIGARETTE SMOKING AS A DEPENDENCE PROCESS. Norman A.

Krasnegor, Ph.D., ed. Discusses factors involved in the onset,

maintenance, and cessation of the cigarette smoking habit.

Includes an agenda for future research.

GPO Stock #017-024-00895-8 $6.00 NTIS PB #297 721/AS $19

24 SYNTHETIC ESTIMATES FOR SMALL AREAS: STATISTICAL WORKSHOP

PAPERS AND DISCUSSION. Jos. Steinberg, ed. Papers from a workshop on statistical approaches that yield needed estimates of

data for States and local areas. Not available from NCDAI.

GPO Stock #017-024-00911-3 $8.00 NTIS PB #299 009/AS $23.50

25 BEHAVIORAL ANALYSIS AND TREATMENT OF SUBSTANCE ABUSE. Norman

A. Krasnegor, Ph.D., ed. Papers on commonalities and

implications for treatment of dependency on drugs, ethanol, food,

and tobacco.

GPO Stock #017-024-00939-3 $5.00 NTIS PB #80-112428 $22

78
26 THE BEHAVIORAL ASPECTS OF SMOKING. Norman A. Krasnegor, Ph.D.,

ed. Reprint of the behavioral section of the 1979 Report of the

Surgeon General on Smoking and Health; introduction by editor.

GPO out of stock NTIS PB #80-118755 $17.50

27 PROBLEMS OF DRUG DEPENDENCE, 1979: PROCEEDINGS OF THE 41ST

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG DEPENDENCE, INC. L.S. Harris, Ph.D., ed. Not available from NCDAI.

GPO Stock #017-024-00981-4 $9.00 NTIS PB #80-175482 $37

28 NARCOTIC ANTAGONISTS: NALTREXONE PHARMACOCHEMISTRY AND

SUSTAINED-RELEASE PREPARATIONS. Robert Willette, Ph.D., and

Gene Barnett, Ph.D., eds. Papers report research on sustainedrelease and long-acting devices for use with the narcotic antagonist naltrexone.

GPO Stock #017-024-01081-2 $7.00 NTIS PB #81-238875 $23.50

29 DRUG ABUSE DEATHS IN NINE CITIES: A SURVEY REPORT. Louis A.

Gottschalk, M.D., et al. Epidemiologic study providing data on

drug-involved deaths and procedures for their investigations.

Not available from NCOAI.

GPO Stock #017-024-00982-2 $6.50 NTIS PB #80-178882 $17.50

30 THEORIES ON DRUG ABUSE: SELECTED CONTEMPORARY PERSPECTIVES.

Dan J. Lettieri, Ph.D.; Mollie Sayers; and Helen Wallenstein

Pearson, eds. Volume presents summaries of the major contemporary theories of drug abuse by each of 43 leading theorists.

GPO Stock #017-024-00997-1 $10.00 Not available from NTIS

31 MARIJUANA RESEARCH FINDINGS: 1980. Robert C. Petersen, Ph.D.,

ed. The text of the 8th Marijuana and Health report to Congress

and the background scientific papers on which it was based.

GPO out of stock NTIS PB #80-215171 $20.50

32 GC/MS ASSAYS FOR ABUSED DRUGS IN BODY FLUIDS. Rodger L. Foltz,

Ph.D.; Allison F. Fentiman, Jr., Ph.D.; and Ruth B. Foltz. A

collection of methods for auantitative analysis of several

important drugs of abuse by gas chromatography- mass spectrometry.

GPO Stock #017-024-01015-4 $6.00 NTIS PB #81-133746 $19

33 BENZODIAZEPINES: A REVIEW OF RESEARCH RESULTS, 1980. Stephen

I. Szara, M.D., D.Sc., and Jacqueline P. Ludford, M.S., eds.

A RAUS (Research Analysis and Utilization System) Review Report

on the abuse liability of the benzodiazepine "tranquilizers."

GPO Stock #017-024-01108-8 $5.00 NTIS PB #82-139106 $13

34 PROBLEMS OF DRUG DEPENDENCE, 1980: PROCEEDINGS OF THE 42ND

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO Stock #017-024-01061-8 $8.00 NTIS PB #81-194847 $34

79
35 DEMOGRAPHIC TRENDS AND DRUG ABUSE, 1980-1995. Louise G.

Richards, Ph.D., ed. Estimates of probable extent and nature of

nonmedical drug use, 1980-1995, based on age structure and other

characteristics of U.S. population.

GPO Stock #017-024-01087-1 $4.50. NTIS PB #82-103417 $13

36 NEW APPROACHES TO TREATMENT OF CHRONIC PAIN: A REVIEW OF MULTIDISCIPLINARY PAIN CLINICS AND PAIN CENTERS. Lorenz K.Y. Ng, M.D.,

ed. A sharing of ideas among active practitioners in the treatment of pain.

GPO Stock #017-024-01082-1 $5.50. NTIS PB #81-240913 $19

37 BEHAVIORAL PHARMACOLOGY OF HUMAN DRUG DEPENDENCE. Travis

Thompson, Ph.D., and Chris E. Johanson, Ph.D., eds. Presents a

growing body of data, systematically derived, on the behavioral

mechanisms involved in use and abuse of drugs.

GPO Stock #017-024-01109-6 $6.50 NTIS PB #82-136961 $25

38 DRUG ABUSE AND THE AMERICAN ADOLESCENT. Dan J. Lettieri,

Ph.D., and Jacqueline P. Ludford, M.S., eds. A RAUS Review

Report, emphasizing use of marijuana: epidemiology, sociodemographic and personality factors, family and peer influence,

delinquency, and biomedical consequences.

GPO Stock #017-024-01107-0 $4.50 NTIS PB #82-148198 $14.50

39 YOUNG MEN AND DRUGS IN MANHATTAN: A CAUSAL ANALYSIS.

Richard R. Clayton, Ph.D., and Harwin L. Voss, Ph.D. Examines

the etiology and natural history of drug use, with special focus

on heroin. Includes a Lifetime Drug Use Index.

GPO Stock #017-024-01097-9 $5.50 NTIS PB #82-147372 $19

40 ADOLESCENT MARIJUANA ABUSERS AND THEIR FAMILIES. Herbert

Hendin, M.D., Ann Pollinger, Ph.D., Richard Ulman, Ph.D., and

Arthur Carr, Ph.D. A psychodynamic study of adolescents

involved in heavy marijuana use, to determine what interaction between family and adolescent gives rise to drug abuse.

GPO Stock #017-024-01098-7 $4.50 NTIS PB #82-133117 $13

41 PROBLEMS OF DRUG DEPENDENCE, 1981: PROCEEDINGS OF THE 43RD

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. A broad review of

current research. Includes treatment issues; chemistry and

pharmacology of abused drugs; efficacy and dependence liability

of new compounds.

Not available from GPO NTIS PB #82-190760 $41.50

42 THE ANALYSIS OF CANNABINOIDS IN BIOLOGICAL FLUIDS. Richard

Hawks, Ph.D., ed. Presents varied approaches to sensitive,

reliable, and accessible quantitative assays for the chemical

constituents of marijuana, for basic researchers in biomedical

and forensic science.

GPO Stock #017-024-01151-7 $5 NTIS PB #83-136044 $16

L.

80
43 PROBLEMS OF DRUG DEPENDENCE, 1982: PROCEEDINGS OF THE 44TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. A collection of

papers which together record a year's advances in drug abuse

research; also includes reports on tests of new compounds for

efficacy and dependence liability.

GPO Stock #017-024-01162-2 $8.50 NTIS PB #83-252-692 $40

47 PREVENTING ADOLESCENT DRUG ABUSE: INTERVENTION STRATEGIES.

Thomas J. Glynn, Ph.D.; Carl G. Leukefeld, D.S.W.; and

Jacqueline P. Ludford, M.S., eds. A RAUS Review Report on a

variety of approaches to prevention of adolescent drug abuse, how

they can be applied, their chances for success, and needed future

research.

Not available from GPO NTIS PB to be assigned

48 MEASUREMENT IN THE ANALYSIS AND TREATMENT OF SMOKING

BEHAVIOR. John Grabowski, Ph.D., and Catherine S. Bell, M.S.,

eds. Based upon a meeting cosponsored by NIDA and the National

Cancer Institute to delineate necessary and sufficient measures

for analysis of smoking behavior in research and treatment

settings.

GPO Stock #017-024-01181-9 94.50

IN PREPARATION

NTIS PB to be assigned

44 MARIJUANA EFFECTS ON THE ENDOCRINE AND REPRODUCTIVE SYSTEMS.

Monique C. Braude, Ph.D., and Jacqueline P. Ludford, M.S., eds.

A RAUS Review Report of animal studies and preclinical and

clinical studies of effects of cannabinoids on human endocrine

and reproductive functions.

46 BEHAVIORAL INTERVENTION TECHNIQUES IN DRUG ABUSE TREATMENT.

John Grabowski, Ph.D.; Maxine L. Stitzer, Ph.D., and Jack E.

Henningfield, Ph.D., eds. Reports on a variety of behavioral

contingency management procedures used in research/treatment

environments.

81
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