In conscious male rats intracerebroventricular infusion of histamine increased the plasma concentrations of ACTH and beta-endorphin immunoreactivity 2.5-fold (P less than 0.01). Gel filtration of plasma revealed two peaks of beta-endorphin immunoreactivity corresponding to beta-endorphin and beta-lipotropin. The two fractions increased almost equally in histamine-stimulated animals, whereas most of the circulating beta-endorphin immunoreactivity in control animals corresponded to beta-endorphin. Central infusion of the H1-receptor agonist 2-thiazolylethylamine and of the H2-receptor agonists dimaprit or 4-methylhistamine increased the plasma ACTH and beta-endorphin immunoreactivity concentrations 2- and 3-fold, respectively (P less than 0.01). Infused intracerebroventricularly, the H2-receptor antagonists cimetidine or ranitidine prevented the histamine-induced increase in plasma ACTH and beta-endorphin immunoreactivity (P less than 0.01), whereas the H1-receptor antagonist mepyramine inhibited the peptide responses by 70% (P less than 0.01). Infused intra-arterially cimetidine or ranitidine inhibited the histamine-induced increase in plasma ACTH by 80% (P less than 0.01) and plasma beta-endorphin immunoreactivity by 45% (P less than 0.05), whereas mepyramine or the other H1-receptor antagonist SKF-93944 inhibited the ACTH response by 50% (P less than 0.05), but had no effect on the beta-endorphin immunoreactivity. The results indicate that histamine increases the release of the pro-opiomelanocortin derived peptides ACTH, beta-lipotropin and beta-endorphin from the anterior pituitary lobe, whereas an effect of histamine on the release of beta-endorphin from the neurointermediate lobe is possible. The effect of histamine seems primarily mediated by H2-receptors, whereas H1-receptors appear to play a minor role.