Anecdotal reports of polydrug abuse in humans using tripelennamine and pentazocine prompted our investigation of drug interactions between tripelennamine, morphine and various synthetic mixed agonist-antagonists in mice. Pentazocine, nalbuphene and butorphanol, at doses of 4.0-8.0 mg/kg, all showed frank or borderline intrinsic antinociceptive activity and potentiated the tripelennamine response, whereas cyclazocine, an experimental compound with very strong mixed agonist-antagonist qualities at 5.0 mg/kg, showed intrinsic antinociceptive activity but was not potentiated by tripelennamine and actually blocked the tripelennamine response. In a comparative study, pentazocine, butorphanol and nalbuphene had no effect on morphine antinociception whereas cyclazocine completely abolished the antinociceptive effects of morphine. Cimetidine blocked the response of cyclazocine, but not nalbuphene, pentazocine or butorphanol. Our findings demonstrate that the mechanism of action of cyclazocine is significantly different from that of the other mixed agonist-antagonists studied. They also suggest possible histaminergic involvement in antinociception, as well as a locus for antinociception separate from the opiate receptor.