The fat component of the meal is the major stimulant of the gastrocolonic response. The aim of this study was to characterize the mechanism of the gastrocolonic response after eating fat in healthy human volunteers. A bipolar clip electrode recorded spike activity (SP) from the distal colon. An immediate increase in colonic spike activity occurred after eating a fat meal (18.0 +/- 3.0 SP/30 min) (p less than 0.02). Spike activity remained elevated for 90 min after eating the fat meal (18.6 +/- 2.7 SP/30 min) (p less than 0.01). The intravenous infusion of naloxone or atropine inhibited the fat-induced increase in colonic motility. Cholecystokinin is a candidate mediator of the fat-stimulated gastrocolonic response. The intravenous infusion of the octapeptide of cholecystokinin (20 ng/kg . h) stimulated an increase in distal colonic spike activity (16.0 +/- 3.7 SP/30 min) (p less than 0.025). Intravenous atropine did not affect stimulation of colonic motility by the octapeptide of cholecystokinin. Continuous infusion of naloxone, however, did inhibit stimulation of colonic spike activity by the octapeptide of cholecystokinin. There was no cross-reactivity between opiate or muscarinic receptors. These data suggest (a) fat stimulation of the gastro-colonic response required a muscarinic and opiate receptor, and (b) octapeptide of cholecystokinin can stimulate colonic motility, but it is not the major mediator of the gastrocolonic response.