The endogenous opioid system is part of a neural circuitry functionally related to alcohol-seeking behaviors. A family history of alcoholism is the strongest predictor of future development of alcohol dependence. This study was designed to evaluate ACTH responses to opioid receptor blockade as a function of family history for alcohol dependence. The nonselective opioid antagonist naloxone stimulates ACTH secretion by blocking opioidergic input on paraventricular corticotropin-releasing factor neurons, thereby providing a methodology for comparing hypothalamic opioid tone between study groups. Sixty nonalcoholic subjects, aged 18-25 yr, were enrolled in a protocol to measure the ACTH response to naloxone. Thirty-two subjects were offspring from families with a high density of alcohol dependence and were designated as family history-positive subjects. Twenty-eight subjects were offspring of nonalcohol-dependent parents and were designated family history-negative subjects. Subjects received naloxone (125 microg/kg) or placebo (0.9% saline) in double blind, randomized order. Plasma ACTH was monitored. Family history-positive men had increased ACTH response to naloxone compared to 1) family history-positive women, 2) family history-negative men, and 3) family history-negative women. Despite differences in plasma ACTH levels after naloxone administration, plasma naloxone concentrations did not differ between study groups. This finding suggests that nonalcoholic male offspring of alcohol-dependent men have altered endogenous opioid activity directed at hypothalamic corticotropin-releasing factor neurons.