Catechol-O-methyltransferase polymorphism alters hypothalamic-pituitary-adrenal axis responses to naloxone: a preliminary report

A common polymorphism in the catechol-O-methyltransferase gene involves a valine to methionine mutation that results in a threefold to fourfold decrease in enzyme activity. This polymorphism has been associated with altered μ-opioid receptor binding potential and prefrontal cognitive performance, as well as risk for several neuropsychiatric conditions. We hypothesized that subjects homozygous for the low-activity allele would have greater hypothalamic-pituitary-adrenal axis responses to opioid blockade than subjects with the high-activity allele. Forty-six healthy adults were genotyped and underwent a procedure in which adrenocorticotropin hormone and cortisol responses to the opioid antagonist naloxone were examined. Findings showed that adrenocorticotropin hormone and cortisol responses were greater in subjects with the methionine/methionine genotype compared to subjects homozygous or heterozygous for the valine allele. These findings suggest that individual differences in catecholamine metabolism may impact hypothalamic-pituitary-adrenal axis function and may play a pharmacogenetic role in responses to naloxone.