The effect of zolantidine dimaleate (ZOL), the first brain-penetrating histamine H2 receptor antagonist, was determined on morphine (MOR) antinociception (ANC) in rhesus monkeys. ZOL (0.75 mg/kg, s.c., given every 30 min), completely attenuated the ANC resulting from the lowest dose of MOR tested (1.0 mg/kg), with no effect on the responses to higher doses (3-10 mg/kg). ZOL had no effect on baseline nociceptive responses in the absence of MOR. Taken with previous studies on the pharmacological specificity of ZOL, the ANC properties of histamine, and more extensive studies in rodents, the present results suggest that opiates like MOR relieve pain in primates by mechanisms that include activation of brain H2 receptors.