Novel Characterization Of Thermal Temporal Summation Response By Analysis Of Continuous Pain Vs Time Curves And Exploratory Modeling

Temporal summation (TS) refers to the increased perception of pain with repetitive noxious stimuli. While thermal TS is generally considered a behavioral correlate of spinal windup, noxious heat pulses also trigger additional sensory processes which were modeled in this study.  Nineteen healthy volunteers (9 females, mean age 29.2, SD 10.5) underwent two identical TS experiments, spaced a week apart. The TS paradigm consisted of 10 identical heat pulses with individualized temperatures at the thenar eminence (0.5Hz). We extracted 3 features from continuous TS response curves: Lag, time to first feel pain; Slope, the rate of pain increase between the first and most painful heat pulse; and Delta, the maximum drop in pain after peak pain is reached. We then examined the within-individual stability of these features, followed by the Pearson’s correlations among these features and between the features and negative affect.  All 3 features were stable over 1 week. Lag and Delta were negatively correlated (r = −0.5, p = 0.042). Slope did not correlate with Lag or Delta, but strongly correlated with a traditional TS measure, first pulse pain and peak pain difference (r = 0.91, p < 0.0001). Negative affects such as trait and state anxiety were negatively correlated with baseline (r = −0.49, p = 0.031) and peak stimulating temperature (r = −0.48, p = 0.039), respectively, suggesting an association between anxiety and greater pain sensitivity.  We were able to decouple spinal windup from other perceptual processes generated by phasic thermal TS paradigms and demonstrate temporal stability of these curve features. These curve features may help better characterize the complex sensory response to noxious heat pulses and serve as biomarkers to profile patients with chronic pain.

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title: Wind-up and neuroplasticity: is there a correlation to clinical pain?
abstract: It is neurophysiologically and neurobiologically verified that the central nociceptive system can undergo changes and become hyperexcitable. Hyperexcitability involves wind-up (exaggerated responses) of dorsal horn neurones which in humans can be studied (temporal summation) by electrophysiological and psychophysical reactions to repeated nociceptive stimuli. Temporal summation occurs if repeated stimuli evoke increasing pain reactions. Human experimental models are adequate to investigate basic aspects and pharmacological modulation of summation and to bridge the gap between basic and clinical sciences facilitating the transfer of knowledge from basic science into the clinic. Human experimental investigations have confirmed animal studies that show that central summation is a potent mechanism in both normal and pathophysiological (hyperexcitable) conditions. Central summation should be considered as a target for the development of new centrally acting analgesics, for designing management regimens to treat intractable pain, and as a possible way of inhibiting surgically-induced afferent barrage from reaching brain centres (subconscious pain) during anaesthesia.

title: Wind‐up and the NMDA receptor complex from a clinical perspective
abstract: More rational treatment of chronic pain depends on increased understanding of the pathophysiological mechanisms underlying the various symptoms and characteristics of chronic pain. Central sensitization of pain represents an important pathophysiological mechanism that has received great attention in recent years. The experimental models used to explore mechanisms of central sensitization include the study of wind‐up in animals and temporal summation of pain in humans. Wind‐up was described more than 30 years ago as progressively increasing activity in dorsal horn cells following repetitive activation of primary afferent C‐fibres. In humans, temporal summation of repeated painful stimuli has been regarded as a psychophysical correlate of wind‐up. This review focuses on the relationship between wind‐up, temporal summation and central sensitization. In particular, the role of NMDA receptor mechanisms in the modulation of wind‐up/temporal summation is discussed. The data presented here indicate that the study of wind‐up and temporal summation has given information about some of the complex mechanisms underlying central sensitization. Both wind‐up and temporal summation appear to be dependent on NMDA receptor activation. The results of clinical trials in patients with chronic pain suggest that the NMDA receptor may represent a new target for modulation of abnormal temporal summation of pain, as well as other characteristics of chronic pain.

title: Characteristics of second pain and flexion reflexes indicative of prolonged central summation.
abstract: Characteristics of first and second pain (human subjects) and flexion reflexes (spinal cats) were studied to assess their consistency with dorsal horn cell responses to cutaneous A and C fiber stimulation. For both experiments, two percutaneous electrical shock intensities were used to activate only A fibers and both A and C fibers. Selective block of ulnar nerve impulses necessary for first (pricking) pain was achieved by pressure to the ventral forearm. During blockade, sensation thresholds to shock and graded von Fry hairs increased progressively. After about 40 min, touch, first pain, and pinprick were no longer perceived, but long-latency (> 1 sec) burning sensations due to intense shocks and strong pinch persisted. Differences in reaction time to first and second pain indicated that second pain was related to impulses conducting between 0.8 and 1.6 m/sec (mean = 1.3 m/sec). Sensations of second pain increased with each successive shock if stimulus frequencies were greater than 0.3/sec. These progressive increases occurred both before and after blockade of first pain but not with shock intensities sufficient only to produce first pain. Second pain could be selectively suppressed by mildly painful clamping of adjacent or contralateral digits. A similar analysis applied to flexion reflexes showed that late (or second) flexion reflexes increased progressively when C fibers were activated and when shock frequency exceeded 0.3/sec. The stimulus intensities and frequencies of shocks producing progressively more intense second pain and late flexion reflexes are consistent with previously observed increases in dorsal horn responses to iterative C fiber stimulation.

title: Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses
abstract: &NA; Psychophysical experiments were carried out on 6 human subjects to determine how first and second pain are influenced by peripheral receptor mechanisms and by central nervous system inhibitory and facilitatory mechanisms. For these experiments, brief natural painful stimuli delivered to the hand were a train of 4–8 constant waveform heat pulses generated by a contact thermode (peak temp. = 51.5°C). The magnitude of first and second pain sensations was estimated using cross‐modality matching procedures and reaction times were determined. The latter confirmed the relationship between first and second pain and impulse conduction in A&dgr; and C noxious heat afferents, respectively. The intensity of first pain decreased with each successive heat pulse when the interpulse interval was 80 sec or less. This decrease was most likely the result of heat induced suppression of A&dgr; heat nociceptors since it did not occur if the probe location changed between successive heat pulses. In contrast, second pain increased in intensity with each successive heat pulse if the interval was 3 sec or less. This summation was most likely due to central nervous system summation mechanisms since it also occurred after blockage of first pain by ulnar nerve compression and when the location of the thermode changed between heat pulses. These observations and their interpretations are supported by our recording of responses of single A&dgr; heat nociceptive afferents, C polymodal nociceptive afferents, and “warm” afferents of rhesus monkeys to similar trains of noxious heat pulses. Their responses to these heat pulses show a progressive suppression. Furthermore, previous studies have shown that wide dynamic range dorsal horn neurons show summated responses to repeated volleys in C fibers (Symbol). These spinal cord summation mechanisms could account for the summation of second pain. Symbol. No caption available

title: Experimental and clinical applications of quantitative sensory testing applied to skin, muscles and viscera.
abstract: Quantification of the human painful sensory experience is an essential step in the translation of knowledge from animal nociception to human pain. Translational models for assessment of pain are very important, as such models can be used in: 1) basic mechanistic studies in healthy volunteers; 2) clinical studies for diagnostic and monitoring purposes; 3) pharmacological studies to evaluate analgesic efficacy of new and existing compounds. Quantitative pain assessment, or quantitative sensory testing (QST), provides psychophysical methods that systematically document alterations and reorganization in nervous system function and, in particular, the nociceptive system. QST is defined as the determination of thresholds or stimulus response curves for sensory processing under normal and pathophysiological conditions. The modern concept of advanced QST for experimental pain assessment is a multimodality, multitissue approach where different pain modalities (thermal, mechanical, electrical, and chemical) are applied to different tissues (skin, muscles, and viscera) and the responses are assessed by psychophysical methods (thresholds and stimulus-response functions). Many new and advanced technologies have been developed to help relieve evoked, standardized, and painful reactions. Assessing pain has become a question of solving a multi-input, multi-output problem, with the solution providing the possibility of teasing out which pain pathways and mechanisms are involved, impaired, or affected.



Many methodologies have been developed for quantitative assessment of pain perception and involved mechanisms. This paper describes the background for the different methods, the use in basic pain experiments on healthy volunteers, how they can be applied in drug profiling, and the applications in clinical practice.

title: Effects of age on temporal summation and habituation of thermal pain: clinical relevance in healthy older and younger adults.
abstract: Although the effects of aging on the experience of clinical pain seem relatively clear, investigations of age-related changes in pain perception using laboratory-based pain assessment procedures have yielded contradictory findings. One potential source of variability in this literature is the type of experimental noxious stimulus that is used. Although thermal pain thresholds are the most commonly reported measure of pain sensitivity, use of suprathreshold stimuli in pain assessment procedures may yield additional, more clinically relevant information concerning the effects of aging on the experience of pain. The present study examined the effects of age on temporal summation of both the intensity and unpleasantness of thermal pain at multiple stimulus temperatures. Specifically, responses to repetitive thermal stimuli delivered to the volar forearm at 47 degrees C, 50 degrees C, and 53 degrees C were assessed in 34 younger (mean age, 22.4 years) and 34 older (mean age, 62.2 years) healthy volunteers. Results suggested that for the 47 degrees C and 50 degrees C stimulus trains, older adults exhibited higher ratings of the intensity and unpleasantness of thermal pain and enhanced temporal summation of thermal pain relative to younger adults. Moreover, thermal pain sensitivity was inversely related to perceptions of general health and to reports of recent clinical pain among younger, but not older, subjects. Collectively these findings may indicate small, although potentially significant, age-related alterations in the plasticity of the central nervous system or endogenous pain-modulatory capacities.

title: Contact heat-evoked temporal summation: Tonic versus repetitive-phasic stimulation
abstract: Temporal summation (TS) is usually evoked by repetitive mechanical or electrical stimuli, and less commonly by tonic heat pain. The present study aimed to examine the TS induction by repetitive‐phasic versus tonic heat pain stimuli. Using 27 normal volunteers, we compared the extent of summation by three calculation methods: start‐to‐end pain rating difference, percent change, and double‐logarithmic regression of successive ratings along the stimulation. Subjects were tested twice, and the reliability of each of the paradigms was obtained. In addition, personality factors related to pain catastrophizing and anxiety level were also correlated with the psychophysical results. Both paradigms induced significant TS, with similar increases for the repetitive‐phasic and the tonic paradigms, as measured on 0–100 numerical pain scale (from 52.9 ± 11.7 to 80.2 ± 15.5, p < 0.001; and from 38.5 ± 13.3 to 75.8 ± 18.3, p < 0.001, respectively). The extent of summation was significantly correlated between the two paradigms, when calculated by absolute change (r = 0.543, p = 0.004) and by regression (r = 0.438, p = 0.025). Session‐to‐session variability was similar for both paradigms, relatively large, yet not biased. As with other psychophysical parameters, this poses some limitations on TS assessment in individual patients over time. The extent of TS induced by both paradigms was found to be associated with anxiety level and pain catastrophizing. Despite some dissimilarity between the repetitive‐phasic and the tonic paradigms, the many similarities suggest that the two represent a similar physiological process, even if not precisely the same. Future clinical applications of these tests will determine the clinical relevance of the TS paradigms presented in this study.

title: Relationships between skin temperature and temporal summation of heat and cold pain.
abstract: Temporal summation of heat pain during repetitive stimulation is dependent on C nociceptor activation of central N-methyl-d-aspartate (NMDA) receptor mechanisms. Moderate temporal summation is produced by sequential triangular ramps of stimulation that control skin temperature between heat pulses but do not elicit distinct first and second pain sensations. Dramatic summation of second pain is produced by repeated contact of the skin with a preheated thermode, but skin temperature between taps is not controlled by this procedure. Therefore relationships between recordings of skin temperature and psychophysical ratings of heat pain were evaluated during series of repeated skin contacts. Surface and subcutaneous recordings of skin temperatures revealed efficient thermoregulatory compensation for heat stimulation at interstimulus intervals (ISIs) ranging from 2 to 8 s. Temporal summation of heat pain was strongly influenced by the ISIs and cannot be explained by small increases in skin temperature between taps or by heat storage throughout a stimulus series. Repetitive brief contact with a precooled thermode was utilized to evaluate whether temporal summation of cold pain occurs, and if so, whether it is influenced by skin temperature. Surface and subcutaneous recordings of skin temperature revealed a sluggish thermoregulatory compensation for repetitive cold stimulation. In contrast to heat stimulation, skin temperature did not recover between cold stimuli throughout ISIs of 3-8 s. Psychophysically, repetitive cold stimulation produced an aching pain sensation that progressed gradually and radiated beyond the site of stimulation. The magnitude of aching pain was well related to skin temperature and thus appeared to be established primarily by peripheral factors.

title: Characteristics of temporal summation of second pain sensations elicited by brief contact of glabrous skin by a preheated thermode.
abstract: Temporal summation of sensory intensity was investigated in normal subjects using novel methods of thermal stimulation. A Peltier thermode was heated and then applied in a series of brief (700 ms) contacts to different sites on the glabrous skin of either hand. Repetitive contacts on the thenar or hypothenar eminence, at interstimulus intervals (ISIs) of 3 s, progressively increased the perceived intensity of a thermal sensation that followed each contact at an onset latency > 2 s. Temporal summation of these delayed (late) sensations was proportional to thermode temperature over a range of 45-53 degrees C, progressing from a nonpainful level (warmth) to painful sensations that could be rated as very strong after 10 contacts. Short-latency pain sensations rarely were evoked by such stimuli and never attained levels substantially above pain threshold for the sequences and temperatures presented. Temporal summation produced by brief contacts was greater in rate and amount than increases in sensory intensity resulting from repetitive ramping to the same temperature by a thermode in constant contact with the skin. Variation of the interval between contacts revealed a dependence of sensory intensity on interstimulus interval that is similar to physiological demonstrations of windup, where increasing frequencies of spike train activity are evoked from spinal neurons by repetitive activation of unmyelinated nociceptors. However, substantial summation at repetition rates of > or = 0.33 Hz was observed for temperatures that produced only late sensations of warmth when presented at frequencies < 0.16 Hz. Measurements of subepidermal skin temperature from anesthetized monkeys revealed different time courses for storage and dissipation of heat by the skin than for temporal summation and decay of sensory intensity for the human subjects. For example, negligible heat loss occurred during a 6-s interval between two trials of 10 contacts at 0.33 Hz, but ratings of sensory magnitude decreased from very strong levels of pain to sensations of warmth during the same interval. Evidence that temporal summation of sensory intensity during series of brief contacts relies on central integration, rather than a sensitization of peripheral receptors, was obtained using two approaches. In the first, a moderate degree of temporal summation was observed during alternating stimulation of adjacent but nonoverlapping skin sites at 0.33 Hz. Second, temporal summation was significantly attenuated by prior administration of dextromethorphan, a N-methyl-D-aspartate receptor antagonist.

title: Sex, gender, and pain: a review of recent clinical and experimental findings.
abstract: Sex-related influences on pain and analgesia have become a topic of tremendous scientific and clinical interest, especially in the last 10 to 15 years. Members of our research group published reviews of this literature more than a decade ago, and the intervening time period has witnessed robust growth in research regarding sex, gender, and pain. Therefore, it seems timely to revisit this literature. Abundant evidence from recent epidemiologic studies clearly demonstrates that women are at substantially greater risk for many clinical pain conditions, and there is some suggestion that postoperative and procedural pain may be more severe among women than men. Consistent with our previous reviews, current human findings regarding sex differences in experimental pain indicate greater pain sensitivity among females compared with males for most pain modalities, including more recently implemented clinically relevant pain models such as temporal summation of pain and intramuscular injection of algesic substances. The evidence regarding sex differences in laboratory measures of endogenous pain modulation is mixed, as are findings from studies using functional brain imaging to ascertain sex differences in pain-related cerebral activation. Also inconsistent are findings regarding sex differences in responses to pharmacologic and non-pharmacologic pain treatments. The article concludes with a discussion of potential biopsychosocial mechanisms that may underlie sex differences in pain, and considerations for future research are discussed.



This article reviews the recent literature regarding sex, gender, and pain. The growing body of evidence that has accumulated in the past 10 to 15 years continues to indicate substantial sex differences in clinical and experimental pain responses, and some evidence suggests that pain treatment responses may differ for women versus men.

title: Pain sensitivity risk factors for chronic TMD: descriptive data and empirically identified domains from the OPPERA case control study.
abstract: Many studies report that people with temporomandibular disorders (TMD) are more sensitive to experimental pain stimuli than TMD-free controls. Such differences in sensitivity are observed in remote body sites as well as in the orofacial region, suggesting a generalized upregulation of nociceptive processing in TMD cases. This large case-control study of 185 adults with TMD and 1,633 TMD-free controls measured sensitivity to painful pressure, mechanical cutaneous, and heat stimuli, using multiple testing protocols. Based on an unprecedented 36 experimental pain measures, 28 showed statistically significantly greater pain sensitivity in TMD cases than controls. The largest effects were seen for pressure pain thresholds at multiple body sites and cutaneous mechanical pain threshold. The other mechanical cutaneous pain measures and many of the heat pain measures showed significant differences, but with lesser effect sizes. Principal component analysis (PCA) of the pain measures derived from 1,633 controls identified 5 components labeled: 1) heat pain ratings; 2) heat pain aftersensations and tolerance; 3) mechanical cutaneous pain sensitivity; 4) pressure pain thresholds; and 5) heat pain temporal summation. These results demonstrate that compared to TMD-free controls, chronic TMD cases are more sensitive to many experimental noxious stimuli at extracranial body sites, and provide for the first time the ability to directly compare the case-control effect sizes of a wide range of pain sensitivity measures.



This article describes experimental pain sensitivity differences between a large sample of people with chronic TMD and non-TMD controls, using multiple stimulus modalities and measures. Variability in the magnitude and consistency of case-control differences highlight the need to consider multiple testing measures to adequately assess pain processing alterations in chronic pain conditions.

title: Women Undergoing Third Line Overactive Bladder Treatment Demonstrate Elevated Thermal Temporal Summation
abstract: We sought to determine whether women with overactive bladder who required third line therapy would demonstrate greater central sensitization, indexed by temporal summation to heat pain stimuli, than those with overactive bladder.  We recruited 39 women with overactive bladder from the urology clinic who were planning to undergo interventional therapy for medication refractory overactive bladder with onabotulinumtoxinA bladder injection or sacral neuromodulation. We also recruited 55 women with overactive bladder who were newly seen at our urology clinic or who responded to advertisements for study participation. Participants underwent quantitative sensory testing using a thermal temporal summation protocol. The primary study outcome was the degree of temporal summation as reflected in the magnitude of positive slope of the line fit to the series of 10 stimuli at a 49C target temperature. We compared the degree of temporal summation between the study groups using linear regression.  Women in the group undergoing third line therapy showed significantly higher standardized temporal summation slopes than those in the nontreatment group (&bgr; = 1.57, 95% CI 0.18–2.96, t = 2.25, p = 0.027). On exploratory analyses a history of incontinence surgery or hysterectomy was associated with significantly greater temporal summation.  In this study the degree of temporal summation was elevated in women undergoing third line overactive bladder therapy compared to women with overactive bladder who were not undergoing that therapy. These findings suggest there may be pathophysiological differences, specifically in afferent nerve function and processing, in some women with overactive bladder.

title: Temporal summation of second pain: Variability in responses to a fixed protocol
abstract: Temporal summation of second pain (TSSP) is relevant for the study of central sensitization, and refers to increased pain evoked by repetitive stimuli at a constant intensity. While the literature reports on participants whose pain ratings increase with successive stimuli, response to a TSSP protocol can be variable. The aim of this study was to characterize the full range of responses to a TSSP protocol in pain‐free adults.

title: Test-retest reliability of thermal temporal summation using an individualized protocol.
abstract: Temporal summation (TS) refers to the increased perception of pain with repetitive noxious stimuli. It is a behavioral correlate of wind-up, the spinal facilitation of recurring C-fiber stimulation. In order to utilize TS in clinical pain research, it is important to characterize TS in a wide range of individuals and to establish its test-retest reliability. Building on a fixed-parameter protocol, we developed an individually adjusted protocol to broadly capture thermally generated TS. We then examined the test-retest reliability of TS within-day (intertrial intervals ranging from 2 to 30 minutes) and between-days (intersession interval of 7 days). We generated TS-like effects in 19 of the 21 participants. Strong correlations were observed across all trials over both days (intraclass correlation [ICC]  = .97, 95% confidence level [CL] = .94-.99) and across the initial trials between days (ICC [A, 1] = .83, 95% CL = .58-.93). Repeated measures mixed-effects modeling demonstrated no significant within-day variation and only a small (5 out of 100 points) between-day variation. Finally, a Bland-Altman analysis suggested that TS is reliable across the range of observed scores. Without intervention, thermally-generated TS is generally stable within day and between days.



Our study introduces a new strategy to generate thermal TS in a high proportion of individuals. This study confirms the test-retest reliability of thermal TS, supporting its use as a consistent behavioral correlate of central nociceptive facilitation.

title: Supra-threshold scaling, temporal summation, and after-sensation: relationships to each other and anxiety/fear
abstract: This study investigated the relationship of thermal pain testing from three types of quantitative sensory testing (ie, supra-threshold stimulus response scaling, temporal summation, and after-sensation) at three anatomical sites (ie, upper extremity, lower extremity, and trunk). Pain ratings from these procedures were also compared with common psychological measures previously shown to be related to experimental pain responses and consistent with fear-avoidance models of pain. Results indicated that supra-threshold stimulus response scaling, temporal summation, and after-sensation, were significantly related to each other. The site of stimulation was also an important factor, with the trunk site showing the highest sensitivity in all three quantitative sensory testing procedures. Supra-threshold response measures were highly related to measures of fear of pain and anxiety sensitivity for all stimulation sites. For temporal summation and after-sensation, only the trunk site was significantly related to anxiety sensitivity, and fear of pain, respectively. Results suggest the importance of considering site of stimulation when designing and comparing studies. Furthermore, psychological influence on quantitative sensory testing is also of importance when designing and comparing studies. Although there was some variation by site of stimulation, fear of pain and anxiety sensitivity had consistent influences on pain ratings.

title: Sex and pain-related psychological variables are associated with thermal pain sensitivity for patients with chronic low back pain.
abstract: Biologic and psychological associations with evoked pain sensitivity have been extensively studied in healthy subjects but not among subjects with clinical pain syndromes. This study involved patients with chronic low back pain and investigated whether: 1) sex differences existed for thermal pain sensitivity; and 2) sex, fear-avoidance beliefs, and/or pain catastrophizing influenced thermal pain sensitivity. Thirty-three consecutive patients enrolled in a pain rehabilitation program completed self-report questionnaires and underwent quantitative sensory testing with an established protocol for thermal stimuli. Women had elevated pain sensitivity for measures of tolerance and temporal summation but not for first pulse response. In the multivariate models predicting thermal pain sensitivity, sex was associated with tolerance, and fear-avoidance beliefs were associated with first pulse response. Sex and pain catastrophizing were associated with temporal summation of thermal pain. Future studies involving clinical samples are necessary to replicate these findings and to explore the involvement of cortical structures.



This study suggests that sex, fear-avoidance beliefs, and pain catastrophizing were associated with thermal pain sensitivity for patients with chronic low back pain. These results corroborated sex differences in tolerance and temporal summation observed in the experimental pain literature for healthy subjects. These results also suggest the potential for these specific pain-related beliefs to be associated with a sensitized state because previous studies have demonstrated their association to clinical pain reports, and this study demonstrated associations with thermal pain sensitivity.

title: Associations among four modalities of experimental pain in women.
abstract: The aim of this study was to investigate the associations among 4 measures of pain induction procedures in 244 healthy women. The procedures were (1) pressure pain threshold assessed over the temporalis muscles, masseter muscles, temporomandibular joints, and the wrists; (2) C fiber-mediated heat pain threshold/tolerance assessed on the skin over the forearm, cheek, and dorsal aspect of the foot; (3) temporal summation of C fiber-mediated heat pain; and (4) ischemic pain threshold/tolerance. Strong associations among pressure pain thresholds at the 4 sites examined (rho = 0.7 to 0.8, P values < or = .001) and among heat pain threshold/tolerance values at the 3 sites examined (rho = 0.6 to 0.9, P values < or = .001) were observed. Pressure pain threshold was moderately correlated with each of the heat pain threshold/tolerance values (rho = 0.2 to 0.4, P values < or = .001). Ischemic pain threshold/tolerance was moderately associated with each of the pressure and heat pain measures (rho = 0.2 to 0.3, P values < or = .05 to .001). Derived measures of the temporal summation of heat pain did not correlate strongly with threshold or tolerance measures of pressure, ischemic, or heat pain. We concluded (1) that for a specific pain modality, the correlation between threshold and tolerance values across anatomic sites is high, and (2) that measures of pressure, ischemic, and thermal pain threshold/tolerance are significantly correlated, although the strength of these associations is moderate. These findings demonstrate that a battery of pain-assessing procedures is required to determine an individual's pain sensitivity profile or phenotype.



By investigating the relationship between pain sensitivity produced by different forms of stimuli, this study demonstrates that a battery of tests should be used to assess an individual's pain sensitivity and one should be careful in making inferences about an individual's sensitivity to pain by using only one pain modality.

title: Response of C fibre nociceptors in the anaesthetized monkey to heat stimuli: correlation with pain threshold in humans.
abstract: 1. Ramped heat stimuli were used to compare the effects of rate of temperature change on the responses of monkey nociceptors and on heat pain threshold in human subjects. Recordings were made from twenty‐five cutaneous C fibre mechano‐heat nociceptors (CMHs) innervating the hairy skin in the anaesthetized monkey. Heat pain thresholds were determined on the volar forearm of eight human subjects using a converging staircase technique. 2. The heat pain threshold decreased as stimulus ramp rate increased. In contrast, the CMH heat threshold, defined as the surface temperature at which the first action potential occurred, increased as stimulus ramp rate increased. Thus, the properties of the heat stimulus that dictate heat pain threshold are different from the properties of the heat stimulus that govern the initiation of a response in nociceptors. 3. Peak discharge frequency of CMHs during the heat ramp increased with stimulus ramp rate. Heat pain threshold was correlated with achievement of a minimum discharge rate in nociceptors (0.5 Hz), rather than with the threshold for action potential initiation.

title: Evidence for two different heat transduction mechanisms in nociceptive primary afferents innervating monkey skin.
abstract: 1. Mechano‐ and heat‐sensitive A fibre nociceptors (AMHs) and C fibre nociceptors (CMHs) in hairy skin (forty‐six AMHs and twenty‐one CMHs) and in glabrous skin (fifty‐nine AMHs and ten CMHs) of anaesthetized monkeys were tested with a 30 s, 53 degrees C heat stimulus, delivered by a laser thermal stimulator (0.1 s rise time, 7.5 mm diameter). 2. Two types of heat response were observed in hairy skin AMHs. Type I AMHs had a peak discharge towards the end of the stimulus, response latencies to heat of up to several seconds, a median heat threshold greater than 53 degrees C, and a mean conduction velocity of 25 m s‐1 (n = 33). Type II AMHs had a peak discharge within 1‐3 s, a mean response latency of 120 ms, a median heat threshold of 46 degrees C, and a mean conduction velocity of 15 m s‐1 (n = 13). Type I AMH fibres were sensitized to heat, whereas heat responses of type II AMHs were suppressed following the intense heat stimulus. 3. In glabrous skin, only type I AMHs were found. The absence of type II AMHs is consistent with the absence of first pain to heat in glabrous skin. 4. C fibre nociceptors in hairy skin had a peak discharge near stimulus onset, a mean response latency of 100 ms and a median heat threshold of 41 degrees C. Heat responses of CMHs in glabrous skin were not significantly different from those in hairy skin. 5. Only type II AMHs had response latencies that were short enough to explain first pain to heat. Heat thresholds of type II AMHs were significantly higher than those of CMHs. 6. These results suggest two different heat transduction mechanisms in nociceptive afferents. For one, heat energy is quickly transduced into action potentials, and the peak discharge is reached soon after stimulus onset. For the other, the transduction of heat is distinctly slower, and the peak discharge occurs near the end of the stimulus. Chemically mediated sensitization may be involved in the second transduction mechanism.

title: C nociceptor activity in human nerve during painful and non painful skin stimulation.
abstract: Percutaneous recordings from more than one hundred single C fibres have been performed in the radial nerve of conscious human subjects. All these fibres belong to the poly-modal C nociceptor group, being excited by mechanical and thermal and also by chemical stimulation. Conduction velocities showed a monophasic distribution with a mean value of 0.86 m/s (SD: 0.17). The mechanical threshold, measured with von Frey hairs, varied between 2.3 and 13.1 g. The receptive field was circular or elliptical; for 33 units the mean axes were 6 mm and 7 mm. Mechanically evoked C fibre discharge even up to more than 10 spikes/s was not necessarily accompanied by pain sensation. Nettle sting evoked an irregular C fibre discharge (maximum 10 spikes/s) accompanied by a pricking and burning sensation; the sensation of itch which was sometimes reported, was not correlated with the discharge frequency. C fibre activation by a chemical irritant (paint remover) also evoked an irregular discharge (maximum 3 to 6 spikes/s), accompanied by pricking and burning pain sensation. The C threshold for radiant heat usually lay below the subject's pain threshold. Increasing skin temperature produced increasing neural firing rate. The mean spike frequency rarely exceeded two spikes/s even with stimuli evoking strong heat pain. The occurrence of subjective heat pain response could be as well predicted from th C fibre spike frequency as from the skin temperature. It is concluded that nociceptive C input provoked by thermal or chemical stimuli correlates well with pain sensation. However, similar C input provided by mechanical stimulation which activates also A beta mechanoreceptors, did not necessarily produce pain sensation.

title: Pain mechanisms: a new theory.
abstract: 'f.he nature of pa.in has been the bject of bitter controversy since the turn of the century (J). There are currently two opposing theories of pain: (i) specificity theory, which holds that pain is a specific modality · e vision or hearing, "with its own central and peripheral apparatus" (2), tnd (ii) pattern theory, which main'ns that the nerve impulse pattern for pain is produced by intense stimulation of nonspecific receptors since "there are no specific fibers and no apecific endings" (3). Both theories derive from earlier concepts proposed by ~on Frey (4) and Goldscheider (5) Ill 1894, and historically they are held to be mutually exclusive. Since it is our purpose here to propose a new theory of pain mechanisms, we shall Slate explicitly at the outset where we agree and disagree with specificity and pattern theories.

title: Central pain mechanisms in chronic pain states--maybe it is all in their head.
abstract: Mechanisms underlying chronic pain differ from those underlying acute pain. In chronic pain states, central nervous system (CNS) factors appear to play particularly prominent roles. In the absence of anatomical causes of persistent pain, medical sub-specialities have historically applied wide-ranging labels (e.g., fibromyalgia (FM), irritable bowel syndrome, interstitial cystitis and somatisation) for what now is emerging as a single common set of CNS processes. The hallmark of these 'centrally driven' pain conditions is a diffuse hyperalgesic state identifiable using experimental sensory testing, and corroborated by functional neuroimaging. The characteristic symptoms of these central pain conditions include multifocal pain, fatigue, insomnia, memory difficulties and a higher rate of co-morbid mood disorders. In contrast to acute and peripheral pain states that are responsive to non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, central pain conditions respond best to CNS neuromodulating agents, such as serotonin-norepinephrine reuptake inhibitors (SNRIs) and anticonvulsants.

title: Pain modulation profile and pain therapy: Between pro- and antinociception
abstract: 0304-3959/$36.0

title: Peripheral acute pain mechanisms.
abstract: Many studies in several species, including humans, have identified a subset of primary afferent nerve fibres that are activated by potential or actual tissue-damaging stimuli. Discharge patterns of these nociceptive afferents faithfully reproduce some aspects of the applied stimuli (e.g. shape of the stimulus-response function) but not others (e.g. time-course of a sustained stimulus). Since primary nociceptive afferents provide the input to the central nervous system, their encoding properties have to be considered when studying central processing. On the other hand, pain perception correlates with some aspects of nociceptor discharges (e.g. fatigue with repetition of brief heat pulses), but not with others (e.g. absolute thresholds). Therefore, the painfulness of a stimulus cannot be deduced from nociceptor discharges alone; central processing needs to be taken into account, particularly central summation. In addition to the immediate responses of nociceptive afferents to external stimulation, acute pain mechanisms also comprise the short-term plasticity of the nociceptive system as a consequence of prolonged noxious stimulation.

title: Comparison of heat and mechanical receptive fields of cutaneous C-fiber nociceptors in monkey.
abstract: 1. Receptive-field properties were investigated in cutaneous C-fiber nociceptive afferents (CMH) responsive to mechanical and heat stimuli. Teased-fiber techniques were used to record from 28 CMHs that innervated the hairy skin of upper or lower limb in anesthetized monkeys. 2. The response to mechanical stimuli was studied with the use of calibrated von Frey probes. The response to heat stimuli was studied with the use of a laser thermal stimulator that provided stepped increases in skin temperature with rise times to the desired temperature near 100 ms. The size of the receptive field (RF) for mechanical stimuli was determined by use of a suprathreshold stimulus that consisted of a 0.5-mm-diam probe that exerted a 200-mN force (10 bar). The size of the heat RF was determined by use of a 49 degrees C stimulus applied to a 7.5-mm-diam area for 1 s. 3. Heat thresholds were determined with an ascending series of stimulus intensities and were found to be stable over many hours: they ranged from 37 to 46 degrees C (mean, 41.1 degrees C). Mechanical thresholds ranged from 1.3 to 7.3 bar (mean, 3.3 bar). There was no correlation between mechanical and heat thresholds. Both thresholds extended well below the corresponding psychophysical pain thresholds in the literature. This suggests that spatial and/or temporal summation of C-fiber input are important for pain induced by either stimulus modality. 4.  RF diameters ranged from 3.3 to 9.6 mm (mean, 4.7 mm); heat RF diameters ranged from punctate (less than 1 mm) to 9.5 mm (mean, 4.3 mm). There was a significant linear correlation between mechanical and heat RF sizes with a slope of one. The distance between the center of the mechanical RF and the center of the heat RF along one axis ranged from 0 to 1.1 mm (mean, 0.4 mm). These data indicate that the heat RFs coincided with the mechanical RFs. 5. Within the mechanical RF determined with the suprathreshold stimuli, all CMHs had one or more punctate areas of maximal mechanical sensitivity where mechanical threshold was lowest. Heat excitability extended greater than 2 mm beyond these mechanically sensitive spots. Because lateral transmission of the heat stimulus is small, this indicates that heat transduction occurs outside the regions of maximal mechanical sensitivity. 6. Both the threshold to heat and the response magnitude at suprathreshold intensities depended on the percentage of the RF area overlapped by the heat stimulus. This indicates that multiple transducer sites probably contribute to the total evoked response.(ABSTRACT TRUNCATED AT 400

title: Myelinated mechanically insensitive afferents from monkey hairy skin: heat-response properties.
abstract: To compare the heat responses of mechanically sensitive and mechanically insensitive A-fiber nociceptors, an electrical search technique was used to locate the receptive fields of 156 A-fibers that innervated the hairy skin in the anesthetized monkey (77 A beta-fibers, 79 A delta-fibers). Two-thirds of these afferents were either low-threshold mechanoreceptors (n = 91) or low-threshold cold receptors (n = 11). Nine A beta-fibers and 41 A delta-fibers were cutaneous nociceptors, and four A delta-fibers innervated subcutaneous tissue. The majority of cutaneous A-fiber nociceptors were heat sensitive (43/50 = 86%). Heat-insensitive cutaneous A-fiber nociceptors consisted of one cold nociceptor, three silent nociceptors, and three high-threshold mechanoreceptors. Two types of response were observed to an intense heat stimulus (53 degrees C, 30 s). Type I (n = 26) was characterized by a long latency (mean: 5 s) and a late peak discharge (16 s). Type II (n = 17) was characterized by a short latency (0.2 s) and an early peak discharge (0.5 s). Type I fibers exhibited faster conduction velocities (25 vs. 14 m/s) and higher heat thresholds (> 53 vs. 47 degrees C, 1-s duration) than type II fibers. The possibility that the type I heat response was a result of sensitization was tested in three fibers by determining the heat threshold to 30-s duration stimuli (42-46 degrees C). For this long stimulus duration heat thresholds were reproducible across multiple runs, and the threshold to the 1-s duration stimulus was not altered by these tests. Thus fibers with a type I heat response were not high-threshold mechanoreceptors that developed a heat response through sensitization. Fibers with a type II heat response had significantly higher mechanical thresholds (median: 15 bar) than fibers with a type I heat response (5 bar). This finding accounts for the observation that type II heat responses were infrequently observed in earlier studies wherein the search technique depended on mechanical responsiveness. Fibers with a type II response exhibited a graded response to heat stimuli, marked fatigue to repeated applications of heat stimuli, and adaptation to sustained heat stimuli similar to that seen in C-fiber nociceptors. First pain sensation to heat is served by type II A-fiber nociceptors that are mechanically insensitive. Type I A-fiber nociceptors likely signal pain to long-duration heat stimuli and may signal first pain sensation to mechanical stimuli.

title: Habituation and short‐term repeatability of thermal testing in healthy human subjects and patients with chronic non‐neuropathic pain
abstract: We investigated habituation effects during thermal quantitative sensory testing (tQST) using 8 repetitive measurements for thermal detection and pain thresholds. The same measurements were repeated two days later. 39 healthy subjects and 36 patients with chronic non‐neuropathic pain syndromes (migraine, tension‐type headache, non‐radicular back pain) were enrolled. The pain intensity was assessed using an 11‐point (0–10) numerical rating scale.

title: Peripheral and central components of habituation of heat pain perception and evoked potentials in humans
abstract: For the neurophysiological examination of nociceptive pathways, contact‐heat evoked potentials (contact‐heat EPs) are elicited by repetitive brief noxious heat stimuli. Suppression of heat responses in primary nociceptive neurons during repetitive stimulation has been shown in animal models in vivo and in vitro. We now investigated whether heat pain and contact‐heat EPs in humans display equivalent signs of habituation. Heat pain and EPs were elicited in 16 volunteers with a contact thermode (30 °C s−1). Heat pulses at three intensities (pain threshold, moderate noxious and maximum available) were applied to the right forearm either by moving the thermode after each pulse to variable locations or when fixed to one location (inter‐stimulus intervals 8–10 s). Contact‐heat EPs consisted of an early negativity in temporal leads (N1), followed by a biphasic response at the vertex (N2‐P2). Pain ratings and contact‐heat EPs (N1 and N2‐P2 components) displayed significant temperature dependence. N2‐P2 correlated positively with ratings. With stimulation at variable locations, both measures slowly decreased with time constants τ of 2 min (ratings) and 12 min (EPs). With stimulation at a fixed location, habituation was much faster for both, ratings (τ = 10 s) and EPs (τ = 33 s). As a consequence, both measures were significantly reduced (p < 0.005) leading to a rightward shift of the stimulus–response function by 5 °C. In conclusion, human heat pain perception and contact‐heat EPs display signs of rapid habituation when stimulation is restricted to a fixed location and thus, reflect fatigue of peripheral nociceptive neurons. Habituation within the central nervous system is slower and less pronounced.

title: An inventory for measuring depression.
abstract: The difficulties inherent in obtaining consistent and adequate diagnoses for the purposes of research and therapy have been pointed out by a number of authors. Pasamanick12in a recent article viewed the low interclinician agreement on diagnosis as an indictment of the present state of psychiatry and called for "the development of objective, measurable and verifiable criteria of classification based not on personal or parochial considerations, but on behavioral and other objectively measurable manifestations." Attempts by other investigators to subject clinical observations and judgments to objective measurement have resulted in a wide variety of psychiatric rating scales.4,15These have been well summarized in a review article by Lorr11on "Rating Scales and Check Lists for the Evaluation of Psychopathology." In the area of psychological testing, a variety of paper-and-pencil tests have been devised for the purpose of measuring specific

title: Development of the Fear of Pain Questionnaire-III
abstract: Fear and/or anxiety about pain is a useful construct, in both theoretical and clinical terms. This article describes the development and refinement of the Fear of Pain Questionnaire (FPQ), which exists in its most current form as the FPQ-III. Factor analytic refinement resulted in a 30-item FPQ-III which consists of Severe Pain, Minor Pain, and Medical Pain subscales. Internal consistency and test-retest reliability of the FPQ-III were found to be good. Four studies are presented, including normative data for samples of inpatient chronic pain patients, general medical outpatients, and unselected undergraduates. High fear of pain individuals had greater avoidance/escape from a pain-relevant Behavioral Avoidance Test with Video, relative to their low fear counterparts, suggesting predictive validity. Chronic pain patients reported the greatest fear of severe pain. Directions for future research with the FPQ-III are discussed, along with general comments about the relation of fear and anxiety to pain.

title: Anxiety sensitivity, anxiety frequency and the prediction of fearfulness.
abstract: A distinction is proposed between anxiety (frequency of symptom occurrence) and anxiety sensitivity (beliefs that anxiety experiences have negative implications). In Study 1, a newly-constructed Anxiety Sensitivity Index (ASI) was shown to have sound psychometric properties for each of two samples of college students. The important finding was that people who tend to endorse one negative implication for anxiety also tend to endorse other negative implications. In Study 2, the ASI was found to be especially associated with agoraphobia and generally associated with anxiety disorders. In Study 3, the ASI explained variance on the Fear Survey Schedule—II that was not explained by either the Taylor Manifest Anxiety Scale or a reliable Anxiety Frequency Checklist. In predicting the development of fears, and possibly other anxiety disorders, it may be more important to know what the person thinks will happen as a result of becoming anxious than how often the person actually experiences anxiety. Implications are discussed for competing views of the ‘fear of fear’.

title: Dynamic Quantitative Sensory Testing to Characterize Central Pain Processing
abstract: Central facilitation and modulation of incoming nociceptive signals play an important role in the perception of pain. Disruption in central pain processing is present in many chronic pain conditions and can influence responses to specific therapies. Thus, the ability to precisely describe the state of central pain processing has profound clinical significance in both prognosis and prediction. Because it is not practical to record neuronal firings directly in the human spinal cord, surrogate behavior tests become an important tool to assess the state of central pain processing. Dynamic QST is one such test, and can probe both the ascending facilitation and descending modulation of incoming nociceptive signals via TS and CPM, respectively. Due to the large between-individual variability in the sensitivity to noxious signals, standardized TS and CPM tests may not yield any meaningful data in up to 50% of the population due to floor or ceiling effects. We present methodologies to individualize TS and CPM so we can capture these measures in a broader range of individuals than previously possible. We have used these methods successfully in several studies at the lab, and data from one ongoing study will be presented to demonstrate feasibility and potential applications of the methods.

title: Pain processing in the human nervous system: a selective review of nociceptive and biobehavioral pathways.
abstract: This selective review discusses the psychobiological mediation of nociception and pain. Summarizing literature from physiology and neuroscience, first an overview of the neuroanatomic and neurochemical systems underpinning pain perception and modulation is provided. Second, findings from psychological science are used to elucidate cognitive, emotional, and behavioral factors central to the pain experience. This review has implications for clinical practice with patients suffering from chronic pain, and provides strong rationale for assessing and treating pain from a biopsychosocial perspective.

title: Pain: an overview
abstract: The neuromatrix theory of pain proposes that pain is a multidimensional experience produced by characteristic "neurosignature" patterns of nerve impulses generated by a widely distributed neural network--the "body-self neuromatrix"--in the brain. These neurosignature patterns may be triggered by sensory inputs, but they may also be generated independently of them. Pains that are evoked by noxious sensory inputs have been meticulously investigated by neuroscientists, and their sensory transmission mechanisms are generally well understood. In contrast, chronic pain syndromes, which are often characterized by severe pain associated with little or no discernible injury or pathology, remain a mystery. The neuromatrix theory of pain, however, provides a new conceptual framework that is consistent with recent clinical evidence. It proposes that the output patterns of the neuromatrix activate perceptual, homeostatic and behavioral programs after injury or pathology, or as a result of multiple other inputs that act on the neuromatrix. Pain, then, is produced by the output of a widely distributed neural network in the brain rather than directly by sensory input evoked by injury, inflammation or other pathology. The neuromatrix, which is genetically determined and modified by sensory experience, is the primary mechanism that generates the neural pattern that produces pain. Its output pattern is determined by multiple influences, of which the somatic sensory input is only a part, that converge on the neuromatrix.

title: Mechanisms of first and second pain in the peripheral and central nervous systems.
abstract: Brief (< 2.0 sec) noxious heat pulses (peak temp = 51.5°C) programmed by a computer and generated by a contact thermode produced first and second pain in human subjects. Measurements of reaction time confirmed that these first and second pains were related to the conduction of impulses in A heat nociceptive and C polymodal nociceptive afferents respectively. Estimates of psychophysical magnitude showed that when four identical heat pulses were applied to the same spot on the hand (interstimulus interval 80 sec), the first pain progressively decreased in perceived intensity whereas the second pain increased with interstimulus intervals of 3 sec or less. The first pain did not decrease if the location of the thermode was changed between each stimulus whereas the summation of the second pain increased under these conditions. Identical trains of noxious heat pulses partially suppressed the responses of A and of C nociceptive afferents. These psychophysical observations and physiologic records indicate that the temporal suppression of heat-induced first pain is related to the suppression of A heat nociceptors and that prolonged temporal summation of second pain is related to summation within the central nervous system. A heat nociceptive afferents and C polymodal nociceptive afferents converge on two types of spinothalamic tract neurons: (1) wide dynamic-range neurons that receive input from non-nociceptive and nociceptive afferents. and (2) nociceptive-specific neurons. Since both types show summation of responses to repeated C fiber stimulation, they can account for summation of second pain.

title: Recommendations on terminology and practice of psychophysical DNIC testing
abstract: a Department of Neurology, Rambam Health Care Campus, Technion Faculty of Medicine, Haifa, Israel b Department of Diagnostic Sciences, UMDNJ, Newark, NJ, USA c Laboratory of Experimental Pain Research, Aalborg University, Aalborg, Denmark d Hopital Ambroise Pare, Boulogne Billancourt, France e Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School Boston, MA, USA f College of Dentistry, University of Florida, Gainesville, FL, USA g Faculty of Health and Welfare Studies, University of Haifa, Haifa, Israel h Department of Molecular Medicine and Surgery, Karolinska Hospital/Institutet, Stockholm, Sweden i Department of Psychology, Bamberg University, Bamberg, Germany j Department of Surgery and Neurosurgery, Faculty of Medicine, Sherbrooke University, Sherbrooke, QC, Canada k Department of Anesthesiology, Radboud University, Nijmegen, Netherlands

title: Stability of behavioral estimates of activity-dependent modulation of pain
abstract: Temporal sensory summation of pain (TSSP) is a proxy measure of windup in humans and results in increased ratings of pain caused by a repetitive, low-frequency noxious stimulus. Aftersensations (ASs) are pain sensations that remain after TSSP has been induced. We examined the within-session and across-session variability in TSSP and AS estimation in healthy participants and in participants with exercise-induced muscle pain in order to determine whether the presence of pain affected the stability of TSSP and ASs. TSSP was estimated by application of 10 repetitive, low-frequency (<0.33 Hz) thermal pulses and measured by the simple slope of pain ratings between the first and fifth pulses. ASs were measured by the presence of any remaining pain sensations up to 1 minute after TSSP was induced. TSSP estimation remained moderately stable in pain-free participants and in participants with pain within a single testing session but demonstrated low stability across sessions in pain-free participants. AS estimation was stable for all groups. Estimation of TSSP and ASs using these protocols appears to be a reliable single-session outcome measure in studies of interventions for acute muscle pain and in experimental studies with healthy participants. This article evaluates the reliability of a commonly used method of estimating TSSP and ASs in both healthy participants and in a clinically relevant model of acute pain. These protocols have the potential to be used as single-session outcome measures for interventional studies and in experimental studies.

title: Individual differences in diffuse noxious inhibitory controls (DNIC): association with clinical variables
abstract: &NA; Laboratory pain research has been criticized as being irrelevant to the clinical experience of pain. Previous findings have been inconsistent with some studies suggesting that experimental pain responses may be related to the reported presence or severity of chronic pain, while others report no such associations. However, few of these studies assess a variety of laboratory pain responses, and none has assessed relationships between clinical pain and diffuse noxious inhibitory controls (DNIC) in healthy subjects. We administered questionnaire measures of pain, quality of life, and psychological variables to a sample of healthy adults participating in a laboratory study of age differences in pain responses. DNIC was not related to other laboratory pain responses, psychological variables, or physiological variables measured in the present study. Regression models predicting health‐related quality of life (e.g. pain, physical functioning) revealed that age, sex, and DNIC responses explained between 10 and 25% of the variance in these dependent measures. Of the laboratory pain variables, only DNIC was the sole consistent predictor of clinical pain and physical health, with greater DNIC responses related to less pain, better physical functioning, and better self‐rated health. In addition, age differences in DNIC appeared to partially mediate age differences in physical functioning. These findings highlight the potential clinical relevance of experimental pain procedures and suggest that DNIC may be the laboratory pain response most closely associated with clinical pain and health‐related variables.

title: Thermal Detection Thresholds of Aδ- and C-Fibre Afferents Activated by Brief CO2 Laser Pulses Applied onto the Human Hairy Skin
abstract: Brief high-power laser pulses applied onto the hairy skin of the distal end of a limb generate a double sensation related to the activation of Aδ- and C-fibres, referred to as first and second pain. However, neurophysiological and behavioural responses related to the activation of C-fibres can be studied reliably only if the concomitant activation of Aδ-fibres is avoided. Here, using a novel CO2 laser stimulator able to deliver constant-temperature heat pulses through a feedback regulation of laser power by an online measurement of skin temperature at target site, combined with an adaptive staircase algorithm using reaction-time to distinguish between responses triggered by Aδ- and C-fibre input, we show that it is possible to estimate robustly and independently the thermal detection thresholds of Aδ-fibres (46.9±1.7°C) and C-fibres (39.8±1.7°C). Furthermore, we show that both thresholds are dependent on the skin temperature preceding and/or surrounding the test stimulus, indicating that the Aδ- and C-fibre afferents triggering the behavioural responses to brief laser pulses behave, at least partially, as detectors of a change in skin temperature rather than as pure level detectors. Most importantly, our results show that the difference in threshold between Aδ- and C-fibre afferents activated by brief laser pulses can be exploited to activate C-fibres selectively and reliably, provided that the rise in skin temperature generated by the laser stimulator is well-controlled. Our approach could constitute a tool to explore, in humans, the physiological and pathophysiological mechanisms involved in processing C- and Aδ-fibre input, respectively.

title: Response of unmyelinated (C) polymodal nociceptors to thermal stimuli applied to monkey's face
abstract: 1. The response of C polymodal nociceptors to thermal and mechanical stimuli applied to the monkey's face was recorded extracellulary in the trigeminal ganglion in rhesus monkeys anesthetized with sodium pentobarbital. Conduction velocities, determined from electrical stimulation of receptive fields (RFs), were in the range for unmyelinated C fibers (mean=0.82 m/s, n=20; SD=+/-0.17). With two exceptions cutaneous RFs were single spots (median=2 mm2; n=37) and usually were identical for thermal and mechanical stimuli. The median force threshold for the sample of units was 1.2 g (von Frey technique; n = 39; range = 0.07-8.5 g). 2. Discharges to thermal stimuli were investigated with a feedback-controlled contact thermode which permitted temperature changes less than or equal 12.0 degrees C/s. Thermal thresholds ranged from 38 degree to 49 degree C (median=46 degrees C; n=37), and maximum discharge frequencies were obtained in the noxious heat range (45-55 degrees C). For a graded series of 5 s duration stimuli from an adapting temperature of 35 degrees C, the number of impulses increased as a monotonic function of stimulus intensity over the range from threshold temperature to 50-53 degrees C. Many stimulus-response functions were positively accelerated, and linear regression analyses showed that most units examined were best fit by nonlinear functions. 3. The typical pattern of activity to 5 s duration temperature shifts into the noxious heat range was a short accelerating burst of impulses followed by deceleration to a lower rate of discharge prior to termination of the stimulus. The temporal profile of the discharge of impulses was virtually identical at different adapting temperatures. In units tested with 30 s duration stimuli at 2-6 degrees C above threshold, the mean frequency of discharge during the final 25 s was 1.46 impulses/s (n=6; SD=+/-0.89). 4. Application of noxious heat stimuli a few degrees above threshold temperature typically sensitized or enhanced the response of the unit to subsequent application of heat stimuli. The signs of sensitization consisted of a decrease in threshold temperature, increased frequency of discharge, decreased latency to the first impulse, and afterdischarges. Units failed to respond throughout the duration of 30 s stimuli if the final temperature exceeded 50 degrees C. Depressed responses were sometimes produced by application of intense (greater than or equal 55 degrees C) stimuli, presumably as a result of partial inactivation of the receptor. 5. In a correlative analysis, the latency and pattern of discharge in a sample of units were compared with escape responses in two monkeys to temperature shifts into the noxious heat range (49 and 51 degrees C). The analysis revealed that the discharge of C polymodal nociceptors alone cannot account for fast escape responses, but the discharge may contribute to escape responses which occur more than 3.5 s after the onset of stimulation.

title: Primary afferent units from the hairy skin of the rat hind limb
abstract: The properties of cutaneous units in the saphenous nerve of the rat have been surveyed. We studied 137 units with myelinated (A-fibre) axons conducting at 4-44 m/s. Of the A-fibre units 66% gave a rapidly adapting discharge following hair movement and could be classified into categories similar to those described previously in cat and rabbit. Two categories predominated: (1) D-hair units with slowly conducting axons and relatively large receptive fields that responded to slow movement of hairs, including down hairs when these were present and (2) G-hair units with larger axons and relatively small fields that were only excited by fast movement of guard hairs. Of the A-fibre units 20% were high threshold mechanoreceptors. As in other species, these had a wide range of conduction velocities and multi-point receptive fields. Other types of A-fibre units found were (a) sensitive, RA units not excited by hair movement, (b) relatively insensitive RA units with diffuse receptive fields and (c) slowly adapting mechanoreceptor units. We studied 149 units with unmyelinated (C-fibre) axons conducting at 0.49-0.89 m/s. Of the C-fibre units 73% were of the polymodal nociceptor type. They had small receptive fields and responded to pressure and heating. The average heat threshold was 47 degrees C (+/- 6 degrees C, S.D.). Units were often not sensitized by suprathreshold heating unlike similar units in cat and rabbit. Other C-fibre units found were sensitive mechanoreceptors (12%), cold thermoreceptors (4%) or were very insensitive or inexcitable (11%). The pattern of innervation of rat limb hairy skin resembles previously studied mammalian species. A notable feature is the large proportion of C-polymodal nociceptor units. In this respect the rat resembles the primate and differs from the cat.

title: Experimental Pain Models Reveal No Sex Differences in Pentazocine Analgesia in Humans
abstract: Accumulating evidence suggests that there are sex differences in analgesic responses to opioid agonists. Several studies using an oral surgery pain model have reported more robust analgesia to κ-agonist–antagonists (e.g., pentazocine, nalbuphine, butorphanol) among women than among men. However, evidence of sex differences in κ-agonist–antagonist effects from studies of experimentally induced pain in humans is lacking.  Therefore, the analgesic effects of intravenous pentazocine (0.5 mg/kg) were determined in healthy women (n = 41) and men (n = 38) using three experimental pain models: heat pain, pressure pain, and ischemic pain. Each pain procedure was conducted before and after double-blind administration of both pentazocine and saline, which occurred on separate days in counterbalanced order.  Compared with saline, pentazocine produced significant analgesic responses for all pain stimuli. However, no sex differences in pentazocine analgesia emerged. Effect sizes for the sex differences were computed; the magnitude of effects was small, and an equal number of measures showed greater analgesia in men than in women. Also, analgesic responses were not highly correlated across pain modalities, suggesting that different mechanisms may underlie analgesia for disparate types of pain.  These findings indicate significant analgesic responses to pentazocine in both men and women across multiple experimental pain assays, and the absence of sex differences contrasts with previous data from the oral surgery model. The most likely explanation for the discrepancy in results is that of differences in the pain assays. These findings are important because they suggest that sex differences in opioid analgesia may be specific to certain types of pain.

title: State-dependent opioid control of pain
abstract: Agonists for the μ-opioid receptor are powerful analgesics and are highly addictive; however, the contribution of the δ- and κ-opioid and opioid receptor-like receptors to motivational states is less clear. Agonists at each receptor modulate neurons in a circuit that selectively controls nociceptive transmission. This circuit can operate in both pain-inhibiting and pain-facilitating states, and the action of opioids contributes to and is determined by the state of the circuit. There is growing evidence that the state of the circuit is determined by aversive and appetitive motivational states, and that this contributes to adaptive behavioural choice.

title: Comparison of responses of warm and nociceptive C-fiber afferents in monkey with human judgments of thermal pain.
abstract: 1. Radiant-heat stimuli of different intensities were delivered every 28 s to the thenar eminence of the hand of human subjects and to the receptive fields (RFs) of 58 "mechanothermal nociceptive" and 16 "warm" C-fibers, most of which innervated the glabrous skin of the monkey hand. A CO2 infrared laser under control via a radiometer provided a step increase in skin temperature to a level maintained within +/- 0.1 degrees C over a 7.5-mm-diameter spot. 2. Human subjects categorized the magnitude of warmth and pain sensations evoked by stimuli that ranged in temperature from 40 to 50 degrees C. The scale of subjective thermal intensity constructed from these category estimates showed a monotonically increasing relation between stimulus temperature and the magnitude of warmth and pain sensations. 3. The mechanothermal fibers had a mean RF size of 18.9 +/- 3.2 mm2 (SE), a mean conduction velocity of 0.8 +/- 0.1 m/s, mean thresholds of 43.6 +/- 0.6 degrees C for radiant heat and 5.95 +/- 0.59 bars for mechanical stimulation, and no spontaneous activity. In contrast, warm fibers had punctate RFs, a mean conduction velocity of 1.1 +/- 0.1 m/s, heat thresholds of less than 1 degrees C above skin temperature, no response to mechanical stimulation, and a resting level of activity in warm skin that was suppressed by cooling. 4. The cumulative number of impulses evoked during each stimulation in the nociceptive afferents increased monotonically as a function of stimulus temperature over the range described by humans as increasingly painful (45-50 degrees C). Nociceptive fibers showed little or no response to stimulus temperatures less than 45 degrees C that elicited in humans sensations primarily of warmth but not pain. In contrast, the cumulative impulse count during stimulation of each warm fiber increased monotonically with stimulus temperature over the range of 39-43 degrees C. However, for stimuli of 41-49 degrees C the cumulative impulse count in warm fibers was nonmonotonic with stimulus temperature. Warm-fiber response to stimuli of 45 degrees C or greater usually consisted of a short burst of impulses followed by cessation of activity. 5. The subjective magnitude of warmth and pain sensations in humans and the cumulative impulse count evoked by each stimulus in warm and nociceptive afferents varied inversely with the number, delivery rate, and intensity of preceding stimulations. 6. The results of these experiments suggest the following: a) that activity in the mechanothermal nociceptive C-fibers signals the occurrence of pain evoked by radiant heat, and that the frequency of discharge in these fibers may encode the intensity of painful stimulation; b) that activity in warm fibers may encode the intensity of warmth at lower stimulus temperatures, but is unlikely to provide a peripheral mechanism for encoding the intensity of painful stimulation at higher stimulus temperatures.

title: Temporal summation of heat pain in temporomandibular disorder patients.
abstract: To compare patients with temporomandibular disorders (TMD) to control subjects on two measures of central processing, ie, temporal summation of heat pain and decay of subsequent aftersensations, following thermal stimulation in both a trigeminal and extratrigeminal area.



A "wind-up" protocol was used in which 19 female TMD patients and 17 female controls were exposed to 15 heat stimuli at a rate of 0.3 Hz. Numeric pain ratings were elicited after the 1st, 5th, 10th, and 15th stimulus presentation and every 15 seconds after final presentation (aftersensations) for up to 2 minutes. In separate trials, the thermode was placed on the thenar eminence of the hand and the skin overlying the masseter muscle.



Groups did not differ with respect to the slope of wind-up when stimulated at either anatomic site, although asymptotic levels occurred sooner for TMD patients than for controls. In analysis of aftersensations, a significant group x site x time interaction was detected, in which TMD patients experienced more prolonged painful aftersensations than controls when stimulated on the skin overlying the masseter muscles.



These results are consistent with the presence of enhanced central sensitivity in TMD and suggest that this sensitivity may be largely confined to the region of clinical pain. This contrasts with conditions such as fibromyalgia, where central sensitivity appears to be widespread.