The gut hormone motilin can initiate the interdigestive migrating motor complex. There are synchronous cyclic changes in plasma motilin-like immunoreactivity (MLI) levels and pancreatico-biliary secretion during the interdigestive period which may be causally related. The purpose of this study was to investigate the role of pancreatico-biliary secretion into the gut as a modulator of plasma MLI concentrations. In six healthy subjects, the mean basal plasma MLI level was 130 +/- 16 pg/ml. Infusion of cholecystokinin octapeptide (CCK-8) stimulated MLI secretion, with an integrated (30 min) response of 2028 +/- 340 pg/min X ml. Intraduodenal perfusion of pancreatico-biliary juice produced a similar increase in plasma MLI, with a 30 min integrated response of 2190 +/- 270 pg/min X ml. Neither enzyme activity, osmolarity, or pH accounted for the response. In six patients with exocrine pancreatic insufficiency, although their mean basal plasma MLI concentration of 205 +/- 44 pg/ml was significantly higher than that observed in healthy subjects, there was no significant plasma MLI increase after CCK-8 infusion. Pancreatic exocrine secretion was severely compromised in these patients, as evidenced by the markedly reduced peak lipase (3.8 +/- 0.6 kU/h) and trypsin (2.4 +/- 0.5 kU/h) outputs. In contrast, infusion of pancreatico-biliary juice obtained from healthy subjects caused a rise in plasma MLI, with a 60 min integrated response of 3912 +/- 1031 pg/min X ml, which was similar to that of 3947 +/- 472 pg/min X ml in healthy subjects. We conclude that there is an undefined factor in pancreatico-biliary juice that stimulates MLI release. A deficiency of pancreatic exocrine secretion may be responsible for the impaired MLI response to CCK-8 stimulation in chronic pancreatitis. Since MLI is known to initiate the formation of the interdigestive migrating motor complexes, diminished motilin release secondary to pancreatic exocrine deficiency may result in disordered gastrointestinal motor activity in patients with chronic pancreatitis.