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

Background & Aims: Substance P, a member of the tachykinin family, is a pro secretory neuropeptide distributed widely throughout the enteric nervous sy stem. 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-, Escheri chia coil 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 antag onists (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 m g/kg), or NK-3 ([Trp(7),beta Ala(8)]NKA(4-10), 1.0 mg/kg) receptor antagoni sts. In a subgroup, extrinsic sensory afferents were ablated by pretreatmen t with capsaicin, Jejunal perfusion, with a plasma electrolyte solution con taining a nonabsorbable marker, was undertaken after exposure to cholera to xin (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 substanc e 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: Pr osecretory pathways involving NK-1 and NK-2 receptors specifically mediate the actions of cholera toxin in the small intestine.