The analgesic effect of morphine in rats, as reflected in elevated thresholds for tail shock induced vocalizations, was markedly potentiated by the antihistamine, diphenhydramine. Intrinsic to the behavioral test paradigm employed are stressors which mobilize endogenous opioid activity as verified by the hyperalgesic effect of naloxone. Diphenhydramine failed to potentiate the analgesic effect of such endogenous opioid activity. The potentiating effect of antihistamines may therefore be mediated by mechanisms whose influence is restricted to systemically administered opiates.