title: Intraluminal acid induces oesophageal shortening via capsaicin-sensitive neurokinin neurons.
abstract: OBJECTIVE
  Intraluminal acid evokes reflex contraction of oesophageal longitudinal smooth muscle (LSM) and consequent oesophageal shortening. This reflex may play a role in the pathophysiology of oesophageal pain syndromes and hiatus hernia formation. The aim of the current study was to elucidate further the mechanisms of acid-induced oesophageal shortening.
  
  
  METHODS
  Intraluminal acid perfusion of the intact opossum smooth muscle oesophagus was performed in vitro in the presence and absence of neural blockade and pharmacological antagonism of the neurokinin 2 receptor, while continuously recording changes in oesophageal axial length. In addition, the effect of these antagonists on the contractile response of LSM strips to the mast cell degranulating agent 48/80 was determined. Finally, immunohistochemistry was performed to look for evidence of LSM innervation by substance P/calcitonin gene-related peptide (CGRP)-containing axons.
  
  
  RESULTS
  Intraluminal acid perfusion induced longitudinal axis shortening that was completely abolished by capsaicin desensitization, substance P desensitization, or the application of the neurokinin 2 receptor antagonist MEN10376. Compound 48/80 induced sustained contraction of LSM strips in a concentration-dependent fashion and this was associated with evidence of mast cell degranulation. The 48/80-induced LSM contraction was antagonized by capsaicin desensitization, substance P desensitization and MEN10376, but not tetrodotoxin. Immunohistochemistry revealed numerous substance P/CGRP-containing neurons innervating the LSM and within the mucosa.
  
  
  CONCLUSIONS
  This study suggests that luminal acid activates a reflex pathway involving mast cell degranulation, activation of capsaicin-sensitive afferent neurons and the release of substance P or a related neurokinin, which evokes sustained contraction of the oesophageal LSM. This pathway may be a target for treatment of oesophageal pain syndromes.
authors.affiliation: GI Division, Hotel Dieu Hospital, 166 Brock Street, Kingston, Ontario, Canada, K7L-5G2. patersow@hdh.kari.net
authors.forename: William G
authors.initials: WG
authors.lastname: Paterson
authors.forename: David V
authors.initials: DV
authors.lastname: Miller
authors.forename: Neil
authors.initials: N
authors.lastname: Dilworth
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Assini
authors.forename: Sandra
authors.initials: S
authors.lastname: Lourenssen
authors.forename: Michael G
authors.initials: MG
authors.lastname: Blennerhassett
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D004947:Esophagus / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D005260:Female; D005744:Gastric Acid / Q000502:physiology*; D008297:Male; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009893:Opossums; D010446:Peptide Fragments / Q000494:pharmacology; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors / Q000502:physiology; D013373:Substance P / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D010446:Peptide Fragments; D018041:Receptors, Neurokinin-2; C069192:neurokinin A(4-10), Tyr(5)-Trp(6,8,9)-Lys(10)-; D013373:Substance P; D015288:Neurokinin A; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin