Our aims were twofold: First, to determine whether motilin and morphine induce "premature" Phase III-like motor activity by acting on receptors located in the wall of the proximal duodenum; second, to characterize the relationship between onset of pharmacologically induced Phase III-like activity and changes in plasma motilin concentration. Five dogs were studied with use of motilin, in doses ranging from 0.01 to 0.8 micrograms/kg, and with use of morphine sulfate, in doses ranging from 2.5 to 80 micrograms/kg, administered by close intra-arterial injection to the proximal duodenum at 40% of the spontaneous migrating motor complex cycle. The minimum effective doses of motilin and morphine necessary to induce premature Phase III-like activity when given intravenously were also determined. Both motilin and morphine induced premature Phase III-like activity in the duodenum, the characteristics of which were similar to those of spontaneous Phase III except that the velocity of migration in morphine-induced Phase III-like activity was greater. The minimum effective dose of each agent was no different whether given intra-arterially or intravenously. The latencies of response to intra-arterial and intravenous administration of each agent were no different. Doses of morphine effective in inducing premature Phase III-like activity led to increases in plasma motilin concentration that occurred only after Phase III-like activity had begun in the duodenum. Our results suggest that humoral initiation of fasting motor activity in the duodenum by motilin and morphine does not occur by stimulation of receptors located within the wall of the duodenum.