The gut and brain peptide neurotensin has been claimed to directly or indirectly stimulate external pancreatic secretion. The purpose of this study was to analyze the mechanism of the neurotensin effect on external pancreatic secretion in the rat. The pancreatic dose-response curve to 40-min venous infusions of neurotensin 1-13 (0.1-10 micrograms/kg-h = 0.06-6 nmol/kg-h) was biphasic; the maximal response occurred at 3.16 micrograms/kg-h and reached approximately 30% of the maximal response to cholecystokinin (CCK). The ED50 was 0.27 micrograms/kg-h (= 0.16 nmol/kg-h) for bicarbonate and 0.45 micrograms/kg-h (= 0.27 nmol/kg-h) for protein output. Pancreatic secretion in response to each neurotensin dose increased steadily during the infusion and peaked 20-40 min after the end of infusion. Atropine and hexamethonium suppressed the stimulatory effect of neurotensin on volume, bicarbonate, and total protein output (p < 0.01). The CCKA receptor antagonist L364718 decreased by 80% sodium and bicarbonate response (p < 0.01) and suppressed protein response (p < 0.01) to neurotensin. Methadone reduced the response to neurotensin by 85%, vagotomy by 80%, and capsaicin pretreatment by 70%. The blockade of alpha 1-, alpha 2-, and beta-adrenoreceptors or of CCKB receptors did not change the neurotensin effect. We conclude that the mechanism of neurotensin stimulation is indirect and neurally mediated and involves nicotinic and muscarinic synapses, CCKA receptors, and, in part, capsaicin-sensitive sensory fibers.(ABSTRACT TRUNCATED AT 250 WORDS)