1. Do genetic differences cause differences in pain sensitivity? COMT val158met Genotype Affects mu-Opioid Neurotransmitter Responses to a Pain Stressor Zubieta et al.

2. Background Transmission of pain signals (and other neural signals) uses neurotransmitters. Pain sensitivity and response to medications varies considerably among people. What causes these differences? Should we change drugs or dosage based on these differences?

3. The mu-Opioid neurotransmitter system is activated by pain, and reduces pain sensation. Opioid drugs include opium and the related compound morphine. The brain produces natural opioids including endorphins and enkephalins, which reduce pain sensation.

4. COMT COMT catechol-O-methyltransferase a protein (enzyme) that regulates neurotransmission. breaks down catecholamine neurotransmitters, thereby stopping or reducing transmission of signals.

5. Humans have a common mutation in COMT, which changes the amino acid at position 158 from a valine (val) to a methionine (met). This mutation reduces the enzymatic activity of COMT by 3 to 4-fold. Do differences in COMT cause differences in pain sensitivity?

6. Recall that we all have two version of each gene, one from each parent. Subjects in the study had –two met (met/met), –two val (val/val) –or one of each (met/val).

7. Hypothesis of pain sensitivity

8. Zubieta's hypotheses Perception of pain and mood effects of pain will be higher in met/met subjects. Previously known that the mu-Opioid neurotransmitter system is activated by pain, and reduces pain sensation. Hypothesize that activation of the mu- opioid system in response to pain will be lower in met/met subjects.

9. Methods 29 healthy volunteers: –15 male, 14 female –20 to 30 years old Genotype subjects to determine val158met polymorphism. Women were studied during the early follicular phase of their menstrual cycle, when estradiol and progesterone levels are lowest, to minimize the possible effects of estradiol on COMT gene expression.

10. Expose subjects to a sustained pain challenge: Masseter muscle in the cheek moves the jaw (mastication / chewing) Continuous infusion of high-salt solution into the masseter muscle causes pain. Continuous infusion of low-salt solution into the masseter muscle does not cause pain. Infuse sufficient volume of solution to reach and maintain a pre-set level of pain intensity

11. Measure activation of mu-opioid receptor- mediated neurotransmission in subject’s brain using positron-emission tomography (PET) scans with the mu-opioid receptor selective tracer [11C]carfentantil. Specifically, measure mu-opioid system activation at several sites in the subjects' brain under pain versus no pain (control) conditions, and calculate difference.

12. Measure perception of pain using McGill pain questionnaire (MPQ) Measure emotional (affect) response using Positive and Negative Affectivity Scale (PANAS)

13. Results The volume of pain-inducing (high-salt) solution required to reach and maintain the pre-set level of pain intensity was –lowest in met/met, –intermediate in met/val, –highest in val/val subjects, met/met subjects are more sensitive to painful stimuli.

14. Sensory and affective measures (MPQ and PANAS) scores were –highest in met/met subjects, –intermediate in met/val, and –lowest in val/val subjects, met/met subjects are more affected by pain.

15. Results met/met subjects had lower activation of the mu-opioid system in response to pain

16. Conclusions This study showed that a common genetic polymorphism of the human COMT enzyme causes distinct differences in subject's physiologic sensitivity to painful stimuli and their psychological responses to such pain. The physiologic and psychological effects were directly correlated. Such genetic polymorphism may be important in drug development and testing, and in the selection of type and dose of drug for patients.