Cholecystokinin (CCK) receptors are found on vagal afferent fibers. In pancreatic acini, CCK receptors exist in high- and low-affinity states. The aim of this study was to identify the vagal CCK-A receptor affinity state that mediates the effect of CCK on pancreatic protein secretion. Using a rat model with a pancreatic-biliary cannula, we studied the effects of CCK-JMV-180 on exocrine pancreatic function. CCK-JMV-180 acts as an agonist on high-affinity CCK receptors and as an antagonist on low-affinity CCK receptors. Infusion of CCK-JMV-180 (22-88 micrograms.kg-1.h-1) caused dose-dependent increases in pancreatic protein secretion, which were blocked by the CCK-A receptor antagonist L-364,718. Acute vagotomy in anesthetized rats and perivagal application of capsaicin in conscious rats abolished pancreatic responses to CCK-JMV-180 at 22 and 44 micrograms.kg-1.h-1. CCK-JMV-180 did not reduce pancreatic responses to CCK octapeptide infusion at 20 and 40 pmol.kg-1.h-1. To demonstrate that endogenously released CCK also acts on high-affinity CCK-A receptors, we showed that in conscious rats intraduodenal infusion of 18% casein produced a threefold increase in protein secretion and elevated plasma CCK levels from 0.7 to 8.4 pM. Infusion of CCK-JMV-180 at 44 micrograms.kg-1.h-1 failed to inhibit pancreatic responses to casein. In separate studies, perivagal application of 1% capsaicin inhibited 95% and 90% of the pancreatic responses to casein and casein combined with intravenous CCK-JMV-180, respectively. The neurotoxic effect of capsaicin on small-diameter sensory vagal fibers was verified by immunohistochemical and retrograde tracing studies. In conclusion, we demonstrated that in contrast to their effect on satiety, which is mediated by vagal low-affinity CCK-A receptors, exogenous CCK and endogenous CCK under physiological conditions act through high-affinity CCK-A receptors to mediate pancreatic protein secretion. These findings suggest that different affinity states of the vagal CCK receptors mediate different digestive functions.