There is some evidence that sleep deprivation (SD) might exert its antidepressant properties by involving endogenous opioid mechanisms. The authors investigated the effects of mu-receptor agonist administration on prolactin release in depressed patients before and after partial SD. Medication-free female depressed inpatients (N=18) were participating in two fentanyl challenge tests after partial SD and undisturbed sleep, 3 days apart in random order. Healthy volunteer women (N=10) were enrolled after full night sleep as comparison subjects. Five of them had placebo trials. Participants were given an intravenous injection of 0.1 mg/70 kg fentanyl at 9:00 AM. The prolactin secretory response to the opiate agonist was investigated for 1 h with serial blood sampling. After a night of undisturbed sleep, fentanyl administration prompted increases in plasma prolactin concentrations with blunted responses found in the depressed group. Following partial SD, the stimulated prolactin secretion of depressed patients increased significantly and was comparable to the response of comparison subjects. These findings suggest that SD acts via an opioid/dopamine-related mechanism. An alternative explanation, based on serotonin involvement is addressed in the discussion.