Plasma concentrations of motilin rise in the first 30 min following the ingestion of a meal in man. To elucidate the mechanisms of this postprandial motilin release, we verified the effect of cerebral stimulation and of gastric distension, both events normally occurring in the early postprandial period, on plasma motilin concentrations. Cerebral stimulation was induced by modified sham feeding (MSF) and gastric distension was done by inflating (with 0, 60, 240, or 480 cc of air) a latex balloon positioned in the gastric fundus. The experiments were performed in healthy volunteers where antroduodenal contractile activity was continuously recorded and where plasma motilin was measured each 10 min. The stimuli were administered 30 min after a phase III of the migrating motor complex (MMC) was seen migrating from the antrum to the duodenum. The interval period between two successive spontaneous peak increases in plasma motilin was estimated at 113.7 +/- 8.5 min in 24 historical control subjects, and it lasted 97 +/- 13 min in the five control volunteers here distended with 0 cc of air (P = NS). This interval was significantly (P < 0.05) shortened with MSF (70 +/- 6.3 min) or following distension with 60 cc (60 +/- 11.4 min), 240 cc (54 +/- 1.9 min) or 480 cc of air (45 +/- 3.2 min). During the 60-min period following the administration of the stimuli, phase IIIs were not seen in the subjects distended with 0 cc of air or in those submitted to MSF. However, balloon distension with 60, 240, or 480 cc of air elicited a premature phase III migrating from the antrum to the duodenum in 3/5, 5/5, and 5/5 of the tested subjects respectively. We conclude that cerebral stimulation by MSF and gastric distension by air-filled balloons were potent stimuli of motilin release, and we therefore suggest that both stimuli could be involved in the process of plasma motilin increase seen after a meal. However, MSF and gastric distension probably acted on different additional modulators since they had opposite effects on antroduodenal motility.