In this paper, the interactions between opiates and antihistaminic compounds, both H1- and H2-blockers, were studied. CD1 mice were used, treated with saline, morphine CHl (5 mg/kg), and 1 or 10 mg/kg of the H1-antihistaminics tripelennamine, chlorpheniramine, diphenhydramine and cyclizine and the H2-antihistaminics ranitidine and cimetidine, all compounds by s.c. route. Using the hot-plate test, it was observed that the two doses of tripelennamine and the higher doses of chlorpheniramine and cimetidine had antinociceptive activity. This increase on analgesia was also observed after chronic treatment with all H1-antihistaminics (10 mg/kg, 3 times daily for 4 days). When antihistaminics were administered with morphine, it was observed that only ranitidine (10 mg/kg) blocked opiate analgesia. On the other hand, previous administration of the opiate antagonist naloxone (1 mg/kg) blocked the antinociceptive action of tripelennamine and chlorpheniramine (10 mg/kg) in control mice. In morphine-dependent mice (by s.c. implantation of a 75-mg morphine pellet), a single injection of diphenhydramine or ranitidine blocked the analgesic action of morphine. Chronic administration of all antihistaminics did not modify morphine analgesia. These data are discussed in relation to the possible binding to the opioid receptors by antihistaminics and their facility in crossing the blood-brain barrier.