11 March 2004

Genes and pains

Oddly enough, this study on genetic dispositions in pain processing came out of studies on genes and alcoholism.


For the current study, Drs. Goldman, Zubieta, and their colleagues used positron emission tomography (PET) targeting the endogenous opioid system to examine the effects of a specific genetic variant on neurochemical brain responses to sustained pain. The researchers also used questionnaires that measure pain-related sensory and affective qualities and internal emotional state to link the neurochemical responses to participants' psychological and physical experience of the pain challenge.

The cathechol-O-methyltransferase (COMT) gene encodes a major enzyme involved in the metabolism of the neurotransmitters dopamine (a chemical messenger involved in motivation and reward) and norepinephrine (a chemical messenger involved in sympathetic nervous system stimulation and inhibition). The val158met variant of the COMT gene codes the substitution of valine (val) by methionine (met) and is associated with a three- to fourfold reduction in COMT enzyme activity. This is a common genetic variant such that the distribution of the three genotypes in the general population is approximately 1/3,1/2 and 1/6. Previous research has linked val158met genotypes to a number of behavioral diseases with complex origins, including obsessive-compulsive disease and schizophrenia.

Drs. Goldman, Zubieta, and colleagues hypothesized that variations in COMT activity conferred by the various val158met genotypes might influence functions regulated by dopamine and adrenergic/noradrenergic (epinephrine/norepinephrine) neurotransmission. One such system, the m-opioid neurotransmitter system, typically is activated in response to prolonged pain or stress. To test their hypothesis, the researchers examined 15 men and 14 women genotyped with respect to the val158met polymorphism. The participants were randomized and blinded during the infusion of painful and nonpainful saline solutions.

As anticipated, the researchers who monitored neurochemical changes observed significant effects of genotype on m-opioid receptor binding and system activation. Compared with heterozygotes (individuals with one copy of each allele), individuals with two copies of the met158 allele and lowest COMT enzyme activity showed diminished regional m-opioid system responses, higher sensory and affective ratings of pain, and a more negative internal state. Persons with two copies of the val158 allele and greater COMT enzyme activity demonstrated opposite effects. The regions of the brain showing these changes included the thalamus, a key pain sensory relay station in the pathway for pain perception, and the amygdala, a region of the brain integral for the emotions of anxiety and distress.