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

Gastroenterology. 2000 Oct;119(4):1037-44. doi: 10.1053/gast.2000.18147.


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(79), substance P, 0.1-3.0 mg/kg; or CP 96,345/4, 0.3-3 mg/kg) or neurokinin (NK)-1 (sendide, 1.0 mg/kg), NK-2 (GR83074, 1.0 mg/kg), or NK-3 ([Trp(7),betaAla(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 microg), LT (25 microg), STa (200 microg/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.

MeSH terms

  • Animals
  • Biphenyl Compounds / pharmacology
  • Chlorides / metabolism
  • Cholera Toxin / pharmacokinetics*
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / innervation
  • Intestinal Mucosa / physiology*
  • Jejunum / innervation
  • Jejunum / physiology*
  • Male
  • Models, Biological
  • Neurokinin-1 Receptor Antagonists
  • Neurons / physiology
  • Peptide Fragments / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Neurokinin-1 / physiology*
  • Receptors, Neurokinin-2 / antagonists & inhibitors
  • Receptors, Neurokinin-2 / physiology*
  • Receptors, Neurokinin-3 / antagonists & inhibitors
  • Receptors, Neurokinin-3 / physiology
  • Sodium / metabolism
  • Substance P / analogs & derivatives
  • Substance P / antagonists & inhibitors
  • Substance P / pharmacology*


  • Biphenyl Compounds
  • Chlorides
  • Neurokinin-1 Receptor Antagonists
  • Peptide Fragments
  • Receptors, Neurokinin-1
  • Receptors, Neurokinin-2
  • Receptors, Neurokinin-3
  • Substance P
  • substance P (4-11), Pro(4)-Trp(7,9)-
  • Cholera Toxin
  • Sodium
  • CP 96345