Genetic Effects on Dopamine Response to an Opiate

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.

- INCLUSION CRITERIA:

1. Male participants between 21-55 years of age.

2. Good health as determined by medical history, physical exam, EKG and lab tests.

3. Current non-smokers or light smokers or e-cigarette users (<20 cig/week) who can
easily abstain from smoking or using e-cigarettes for 1-2 days/week.

4. Current non-drinkers or social drinkers who do not meet past or current DSM IV
criteria for alcohol abuse or alcohol dependence.

5. An equal number of final participants will be of OPRM1 118 A/A vs. 118A/G or
118G/G genotype. This means that after the first group (n40) is complete then
only participants with the required genotype for the other group will be
included.

6. Prior opiate use, at least one experience with one of the opiates listed in
Appendix 1 of the protocol.

7. Comprehension/fluency with English Language.

EXCLUSION CRITERIA:

1. Current or prior history of any significant disease, including cardiovascular,
respiratory, gastrointestinal, hepatic, renal, endocrine, or reproductive disorders,
or a positive hepatitis or HIV test at screening, disorders that could make
administration of an opiate more risky (e.g., asthma, COPD, sleep apnea, or other
breathing disorders; liver or kidney disease; thyroid disorder; trouble swallowing, or
a blockage in the digestive tract (stomach or intestines); neurologic disorders (e.g.,
a history of head injury or brain tumor, epilepsy or other seizure disorder, CVA,
migraine in treatment, etc.); low blood pressure; hypertension; neuromuscular
disorder; gallbladder disease; Addison's disease or other adrenal gland disorders;
enlarged prostate, urination problems)

2. Current Axis-I psychiatric illness as determined by the Structured Clinical Interview
for DSM IV disorders (SCID).

3. Current or prior history of any alcohol or drug dependence as determined by the
Structured Clinical Interview for DSM IV disorders (SCID).

4. Positive result on urine screen for illicit drugs.

5. Medication Use:

1. Current chronic prescription or over the counter medications or use of
prescription or OTC medications known to interact with dopamine receptors within
2 weeks of the study

2. Drugs known to inhibit or induce enzymes that metabolize opiates should not be
used for 4 weeks prior to the study. These include chlorzoxazone, isoniazid,
metronidazole and disulfiram.

3. Cough-and-cold preparations that contain anti-histamines or opiate pain medicines
will be withheld for at least 72 hours prior to each study session.

4. Drugs that may interfere with the BOLD MRI signal within 2 weeks of the study.
These include, but may not be limited to: muscle relaxants or respiratory,
cardiovascular or anticonvulsant medications

6. Morbid obesity (BMI >40 kg/m2)

7. Previous negative effects of opioid administration

8. Presence of certain implanted devices (cardiac pacemaker or neurostimulator, some
artificial joints, metal pins, surgical clips or other implanted metal parts), body
morphology, or claustrophobia. Justification: Implanted devices may increase the risk
of MRI scanning and/or adversely affect the quality of the data; body morphology may
prevent optimal positioning in the scanner and thus affect the quality of the data;
participants with claustrophobia may find the MRI scan too unpleasant and may exhibit
excess movement that will adversely affect the quality of the data. Assessment
tool(s): Prospective participants will fill out an MRI screening questionnaire and
undergo an interview with an MR technologist. Questions concerning suitability for
scanning will be referred to the Medical Advisory Investigator. Prospective
participants will be questioned about symptoms of claustrophobia and placed in the
mock scanner during their first visit to assess for possible difficulty tolerating the
confinement of the scanner and for ability to fit into the scanner.

9. Conditions restricting participant's ability to lie flat for up to two hours (such as
coagulopathies, superficial or deep vein thrombosis, or musculoskeletal
abnormalities). Justification: PET scanning sessions require participants to lie flat
on their backs and remain perfectly still for approximately two hours. Therefore,
conditions that would make that difficult (e.g., chronic back pain, significant
scoliosis) or dangerous (e.g., familial hypercoagulability syndrome, history of
thrombosis) will be exclusionary. Assessment tool(s): History and physical examination
by a qualified IRP clinician, supplemented with a trial of lying in the mock scanner
to assess comfort.

10. Head trauma leading to loss of consciousness for more than 5 min or hospitalization

11. Exposure to ionizing radiation from research studies that, in combination with the
study tracer, would result in cumulative exposure of >5 rem within the previous 12
month period

12. Self-reported and/or observed signs, symptoms, or diagnosis of Raynaud's or Buerger's
disease (e.g., pain in hands or feet at times of rest, during/following cold exposure
or stress, any significant color changes in hands or toes). Additionally, medical
staff will be present to watch for these symptoms during the actual cold pressor test.