In this report, we determined whether leptin could modify the exocrine pancreatic secretion of anaesthetized rats in vivo. Intravenous injection of recombinant murine leptin resulted in a time- and dose-dependent stimulation of exocrine pancreatic secretion, maximally observed with 30 nmol/kg of leptin. This stimulation of pancreatic water, bicarbonate, and protein output was abolished by atropine, hexamethonium, L364,718 ([3S(-)-N-(1,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine]), a cholecystokinin CCK(1) receptor antagonist or perivagal capsaicin pretreatment, but unaffected by the CCK(2) receptor antagonist L365,260 ([3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3yl)-N'-(3-methylphenyl)urea]). In addition, the physiological dose of 3 nmol/kg leptin, ineffective per se, potentiated the secretory effect of 45 pmol/kg of cholecystokinin octapeptide (CCK-8) on exocrine pancreatic secretion. Furthermore, intraperitoneal leptin induced a rapid increase in plasma CCK levels in vivo in the rat. In conclusion, exogenous leptin can modulate exocrine pancreatic secretion through mechanisms involving CCK(1) receptors and capsaicin-sensitive afferent fibres in the rat. Whether this may have a physiological relevance in the postprandial regulation of exocrine pancreatic secretion and thus in nutrient digestion will require further investigations.