Do genetic differences cause differences in pain sensitivity

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 subjects brain using
  positron-emission tomography (PET) scans with the
  mu-opioid receptor selective tracer
  11Ccarfentantil.
• 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.