Genetic Effects on Dopamine Response to an Opiate
Condition: Polymorphism-Genetic; Pain; Addiction
MeSH terms: Behavior, Addictive
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

      - Small differences in genes may alter responses to drugs. One gene that has different forms
      is the mu opioid receptor gene. People with one form of this gene are more sensitive to
      alcohol. People with a different form are sometimes more sensitive to pain. Morphine and
      other prescription pain pills produce pain relief by acting at the mu opioid receptor.
      Researchers want to see the effect of morphine on brain reward and subjective effects.
      Morphine is a strong but short-acting pain medication that is sometimes used for anesthesia
      during surgery.

      Objectives:

      - To compare the effect of morphine on brain measures of dopamine release using imaging.

      Eligibility:

      - Individuals between 21 and 55 years of age who have previously taken pain pills prescribed
      to treat pain from a medical or dental procedure.

      Design:

        -  This study has a screening phase and a study phase. The screening phase involves one or
           two visits of 5 to 6 hours. The study phase consists of 4 study visits. Each study visit
           will take about 8 hours.

        -  Participants will be screened with a medical and psychiatric history and physical exam.
           They will be asked about drinking and drug-taking history, and any family history of
           alcoholism or drug abuse. Blood, urine, and breath samples will be collected.

        -  During the first study visit, an MRI scan may be performed, questionnaires completed,
           and a blood sample collected for genetic testing.

        -  During study visit 2, participants will test their pain sensitivity by placing one hand
           in cold water. Pupil diameter will be measured after the sensitivity test. After a blood
           sample is taken, participants will receive the morphine or a salt solution. The
           sensitivity test and pupil diameter test will be repeated. Final blood samples will be
           collected. A brief physical exam will also be performed.

        -  During study visits 3 and 4, participants will receive morphine or a salt solution
           during a PET scan. Questionnaires to assess subjective effects will be administered.
           Final blood samples will be collected. A brief physical exam will also be performed.

        -  Participants will stay in the clinic until the effects of the drug have worn off after
           study visits 2, 3, and 4.

        -  About 1 week after the study session, participants will have a follow-up phone call.
    

Detailed description: 
      Objectives

      Mesolimbic dopamine (DA) release is a key signal for drug reward, and endogenous opioids are
      thought to exert their effects in part by modulating the activity of this system. A
      functional µ-opioid receptor (OPRM1) A118G single nucleotide polymorphism (SNP) has been
      associated with increased risk for heroin addiction in some studies. This polymorphism has
      been shown to confer differential pain sensitivity and to alter the release of DA following
      an alcohol challenge. The objective of this study is to examine the role of the A118G OPRM1
      polymorphism for responses to a challenge of an opiate (morphine) with regard to
      psycho-physiological variables measured in the laboratory and for brain dopamine release
      measured by [11C]raclopride PET.

      Study Population

      Healthy male participants who have had experience with oral prescription analgesics (e.g.,
      Oxycontin, Vicodin, Percocet, oxycodone) will be recruited for the study. These volunteers
      will be screened to obtain samples of two groups of subjects: 1) persons homozygous for the
      major 118A allele (118AA genotype); 2) persons carrying one or two copies of the variant 118G
      allele (118AG or 118GG genotype, hereafter called 118GX). We will recruit up to 120
      participants to obtain 40 completers per genotype for the study.

      Design

      We will compare the response of these groups to a challenge with morphine given
      intravenously. Participants will receive a standardized IV challenge of morphine (10.0 mg/70
      kg over 1 minute; morphine concentration 2 mg/ml). Pre and post injection measures will be
      made in two areas: 1) subjective response as measured by standardized questionnaires, and 2)
      measures of physiological response, including pupil response to light, respiratory rate,
      oxygen saturation and a pain rating from putting a hand in cold water and blood chemistries.
      In addition, during this visit, participants will wear the AutoSense mobile physiological
      monitor; parameters measured by AutoSense include respiration rate, heart rate, heart-rate
      variability, skin conductance, and activity level. The injection will be repeated in all
      participants in the PET scanner, once with morphine and once with normal saline. Dopamine
      release will be assessed by determining the difference between the binding potential for
      [11C]raclopride, a positron emitter labeled ligand which binds preferentially to D2 receptors
      during saline administration and its binding potential during morphine administration.

      Outcome measures

      We hypothesize that 118GX subjects will have significantly different subjective response to
      the challenge than 118AA subjects as observed in participants receiving alcohol in a similar
      study (Ramchandani et al. 2011). However, the genotype effect on the response may be opposite
      from the effect of genotype on the alcohol response. We also hypothesize that the PET studies
      with [11C]raclopride will show that 118GX subjects have less dopamine release during morphine
      administration than 118 AA subjects.
    

Intervention name(s): Morphine; Placebo
Intervention type(s): Drug; Drug
Intervention MeSH terms: Morphine
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Crossover study - participants receive active and placebo treatments in randomized order.
Masking: Double (Participant, Investigator)
Primary purpose: Other
Keywords: Opiate Receptor; Genotype; PET Imaging