OBJECTIVE Recently we showed that doses of cholecystokinin octapeptide (CCK-8) that produce physiological plasma CCK levels act via stimulation of afferent vagal pathway to mediate pancreatic enzyme secretion. In this study we investigated if endogenous CCK also acts via similar pathway. METHODS In anesthetized rats, plasma CCK levels were elevated by diversion of bile pancreatic juice and duodenal casein feeding. The effects of acute vagotomy as well as that of chemical ablation of the afferent vagal pathway on pancreatic enzyme secretion evoked by increased endogenous plasma CCK levels were investigated. RESULTS Diversion of bile pancreatic juice elevated plasma CCK levels from a basal level of 0.6 +/- 0.1 pmol/L to 8.9 +/- 2.1 pmol/L and caused a more than twofold increase in pancreatic protein secretion. Similar increases in plasma CCK levels and pancreatic secretion were observed with duodenal administration of casein. Vagotomy or perivagal application of capsaicin, a sensory neurotoxin, abolished increases in pancreatic secretion but not plasma CCK levels in response to diversion of bile pancreatic secretion or duodenal administration of casein. In contrast, pancreatic protein responses to 2-deoxy-D-glucose, a central vagal stimulant, remained intact in rats with perivagal capsaicin treatment indicating capsaicin did not affect efferent vagal function. CONCLUSIONS Endogenous CCK under physiological conditions act via stimulation of vagal afferent pathway to mediate pancreatic enzyme secretion.