Neurokinin 1 and 2 receptors mediate cholera toxin secretion in rat jejunum

Background & Aims: Substance P, a member of the tachykinin family, is a prosecretory neuropeptide distributed widely throughout the enteric nervous system. Implicated in inflammatory states, its role in enterotoxigenic water and electrolyte secretion is unclear. We assessed the effect of substance P antagonists and neurokinin receptor antagonists on cholera toxin-, Escherichia coli heat-labile enterotoxin (LT)-, and heat-stable enterotoxin (STa)-induced water secretion in an in vivo rat jejunal perfusion model. Methods: Anesthetized adult male Wistar rats were pretreated with substance P antagonists (D-Pro(2), D-Trp(7,9), substance P, 0.1-3.0 mg/kg; or CP 96,345/4, 0.3-3 mg/kg) or neurokinin (NH)-1 (sendide, 1.0 mg/kg), NK-2 (GR83074, 1.0 mg/kg), or NK-3 ([Trp(7),beta Ala(8)]NKA(4-10), 1.0 mg/kg) receptor antagonists. In a subgroup, extrinsic sensory afferents were ablated by pretreatment with capsaicin, Jejunal perfusion, with a plasma electrolyte solution containing a nonabsorbable marker, was undertaken after exposure to cholera toxin (25 mu g), LT (25 mu g), STa (200 mu g/L), or saline. Results: Cholera toxin-induced water and electrolyte secretion was inhibited by the substance P antagonists and the NK-1 and NK-2 receptor antagonists, but not by the NK-3 receptor antagonist or by pretreatment with capsaicin. Neither LT- nor STa-induced secretions were affected by the pretreatments, Conclusions: Prosecretory pathways involving NK-1 and NK-2 receptors specifically mediate the actions of cholera toxin in the small intestine.