The participation of the central histaminergic system in basal and opioid-induced prolactin secretion in male rats was investigated. 2. Central injections of cimetidine, an H2 antihistaminic, reduced basal plasma prolactin levels from 5.08 +/- 0.76 to 3.11 +/- 0.50 ng/ml (N = 10) while diphenhydramine, an H1 antihistaminic, had no effect. 3. Intracerebroventricular injections of FK 33824, a synthetic opioid peptide, produced a dose-dependent increase of prolactin secretion. This effect was partially blocked (-50%) by pretreatment with 20 ng diphenhydramine 15 min before administration of the opioid peptide. Cimetidine pretreatment failed to modify the prolactin rise in this case. 4. We conclude that brain histaminergic pathways exert a stimulatory tone on basal prolactin secretion which is mediated by H2 receptors and that the opioid-induced prolactin rise depends at least in part on activation of H1-histamine receptors.