Feb. 21, 2003 A common genetic variant influences individual responses and adaptation to pain and other stressful stimuli and may underlie vulnerability to many psychiatric and other complex diseases, reports David Goldman, M.D., Chief, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, and colleagues at NIAAA and the University of Michigan. COMT val158met Genotype Affects m-Opioid Neurotransmitter Responses to a Pain Stressor appears in the February 21 issue of Science (299:1240, 2003).
"Emotional response to stress contributes in many drinkers to the development of alcoholism," said George Kunos, M.D., Ph.D., Scientific Director, Division of Intramural Clinical and Biological Research, NIAAA. "Dr. Goldman and his colleagues have uncovered a genetic explanation for why some individuals and groups may be especially susceptible to consuming alcohol and to increasing their consumption in response to stress."
Earlier reports by first author Jon-Kar Zubieta, M.D., Ph.D., Department of Psychiatry and Mental Health Research Institute and Department of Radiology, University of Michigan (Science 293:311, 2001) and others showed that responses to pain vary considerably from one person to another, with some of the difference in sensitivity attributable to genetic factors. Subsequent work showed that some of these effects were due to gender-related factors (Journal of Neuroscience 22:5100, 2002). 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.
"These data emphasize the need for a systems-level approach to neurobiological processes whereby genetic variation, neuronal functional measures, and phenotypic traits [all physical qualities of the behaving organism] are fully integrated," the authors concluded.
The National Institute on Alcohol Abuse and Alcoholism, a component of the National Institutes of Health, U.S. Department of Health and Human Services, conducts and supports approximately 90 percent of U.S. research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems and disseminates research findings to science, practitioner, policy making, and general audiences.
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