Neurokinin 1 and 2 receptors mediate cholera toxin secretion in rat jejunum.
OBJECTIVE
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.
Turvill
J L
JL
Digestive Diseases Research Centre, St. Bartholomew's and The Royal London School of Medicine and Dentistry, London, England. JLTurvill@email.msn.com
Connor
P
P
Farthing
M J
MJ
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism; D002772:Cholera Toxin / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D007583:Jejunum / Q000294:innervation / Q000502:physiology*; D008297:Male; D008954:Models, Biological; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D013373:Substance P / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D001713:Biphenyl Compounds; D002712:Chlorides; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D013373:Substance P; C045505:substance P (4-11), Pro(4)-Trp(7,9)-; D002772:Cholera Toxin; D012964:Sodium; C066892:CP 96345