The combined action of morphine and dextromethorphan on the superior mesenteric artery was investigated in this study. The artery was cut into rings, placed in a muscle bath and mounted to a force transducer for recording tension. Rings preconstricted with 1 microM phenylephrine produced a dose-dependent relaxation to graded doses of dextromethorphan but showed no response to morphine. An equimolar combination of morphine and dextromethorphan exhibited a marked synergism quantitated by a factor of 3.7 (1.8-7.7, 95% CI). Naloxone, which had no effect on the dextromethorphan dose-response relation, abolished the synergism. Removal of the endothelium produced a slight attenuation of the morphine-dextromethorphan synergism, but the magnitude of this attenuation was the same when dextromethorphan alone was examined in the denuded preparation. In contrast to the marked synergism seen in the mesenteric artery preparation, similar experiments on the carotid artery and the aorta produced only additive interactions.