In rats under a mild stress of restraint the interaction between central opioid receptors and histaminergic stimulation of the pituitary-adrenocortical activity was investigated indirectly through corticosterone secretion. In order to avoid a possible direct action on adrenal glands, all the tested drugs were administered intracerebroventricularly (icv). Naloxone an opioid antagonist and cimetidine, a H2- and mepyramine a H1-receptor antagonists were given 15 min before histamine and histamine agonists. One hour after histaminergic drug injection the rats were restrained for 10 min and decapitated. Histamine, 2-pyridylethylamine (PEA), a histamine H1-receptor agonist, and 4-methylhistamine (MeHA) and dimaprit, H2-receptor agonists, significantly intensified the stress-induced increase in serum corticosterone levels. Naloxone, given alone icv or ip, did not substantially alter the stress-induced corticosterone response. Like mepyramine naloxone abolished the corticosterone response to PEA in stressed rats. Naloxone also decreased significantly, though not totally, the corticosterone response to MeHA, dimaprit and histamine, its efficiency being similar to that of cimetidine, a H2-receptor antagonist. These results suggest that in stressed rats central opioid receptors are considerably involved in the histamine H1-receptor - and, to a lesser degree, in the H2-receptor stimulation of the hypothalamo-pituitary-adrenocortical axis.