Abstract The present study investigated the effect of interactions between histamine receptor agents and the opioid peptidergic system on memory retention of passive avoidance learning in rats. Post-training intracerebroventricular (i.c.v.) injections were carried out in all the experiments. Administration of histamine (20 μg/rat) reduced, but the histamine H 1 receptor antagonist, pyrilamine (20 and 50 μg/rat), and the histamine H 2 receptor antagonist, cimetidine (10 and 50 μg/rat), increased memory retention in rats. The histamine receptor antagonists decreased the response induced by histamine. Morphine (1–10 μg/rat) reduced, while pentazocine (5 and 10 μg/rat) or the opioid receptor antagonist, naloxone (5 and 15 μg/rat), increased memory retention. The combination of histamine with morphine showed potentiation. Effects of pyrilamine and cimetidine were attenuated by morphine. The responses to pentazocine and naloxone also were decreased by histamine. It is concluded that the histaminergic system has an interaction with opioidergic system that is involved in the memory retention process.