"Emotional response to stress contributes in many drinkers to the development of alcoholism," said George Kunos, M.D., Ph.D., of the National Institutes of Health. "Dr. [David] 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 work involving lead author Jon-Kar Zubieta, M.D., Ph.D., showed that
responses to pain vary considerably from 1 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.

For the current study, the American research group used positron emission tomography focused on the endogenous opioid system to examine the effects of a specific allele on neurochemical brain responses to sustained pain. The researchers 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 metabolism of dopamine and norepinephrine. The allele abbreviated as 'val 158 met' results in a protein containing methionine instead of valine at a particular amino acid position. Presence of the abnormal amino acid sequence is associated with a 3-fold to 4-fold decrease in enzyme activity. Previous research has linked 'val 158 met' - containing genotypes to a number of behavioral diseases with complex origins, including obsessive-compulsive disorder and schizophrenia.

The group hypothesized that variations in enzyme activity caused by heterozygous or homozygous genotypes could influence functions regulated by dopamine or norepinephrine. One such system, the mu-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 in terms of the 'val 158 met' allele. The participants were randomized and blinded during infusion of painful and non-painful saline solutions.

As anticipated, the researchers who monitored neurochemical changes observed significant effects of genotype on mu-opioid receptor binding and system activation. Compared with heterozygotes, homozygous people had the lowest level of enzyme activity and demonstrated diminished regional mu-opioid system responses, higher sensory and affective ratings of pain, and a more negative internal state. Persons with two copies of the normal (valine) allele had greater enzyme activity and demonstrated opposite effects. The involved brain regions according to imaging with positron emission tomography included the thalamus and the amygdala.

"These data emphasize the need for a systems-level approach to neurobiological processes whereby genetic variation, neuronal functional measures, and phenotypic traits are fully integrated," the authors concluded.