title: Endogenous prostaglandin I2 regulates the neural emergency system through release of calcitonin gene related peptide.
abstract: BACKGROUND
  We previously reported that endogenous prostaglandin I(2), generated by a mild irritant, sensitised calcitonin gene related peptide (CGRP) containing sensory nerves and facilitated the release of CGRP and gastric mucosal protection against ethanol. Administration of capsaicin also inhibited ethanol induced gastric mucosal injury through immediate release of CGRP from primary sensory neurones, which is termed the neural emergency system. In the present study, we tested whether endogenous prostaglandin I(2) also modulates the cytoprotective action of capsaicin using prostaglandin I receptor knockout mice (IP(-/-)).
  
  
  METHODS
  The stomachs of IP(-/-) or their wild-type counterparts (IP(+/+)), anaesthetised with urethane (1.225 g/kg), were doubly cannulated from the oesophageal and duodenal sides, and the gastric mucosa was perfused (1 ml/min) with physiological saline. Perfusate was changed to 50% ethanol alone, or 50% ethanol containing capsaicin (16 approximately 1600 micro M). The injured area was estimated at the end of each perfusion experiment. In some animals, CGRP-(8-37), a CGRP antagonist (0.3 mg/kg), or indomethacin (1 mg/kg) was intravenously injected before perfusion of 50% ethanol containing capsaicin.
  
  
  RESULTS
  Capsaicin inhibited the injured area in a dose dependent manner. Fifty per cent ethanol containing capsaicin (480 micro M) immediately increased intragastric levels of CGRP although 50% ethanol alone did not. The protective action of capsaicin (480 micro M) against ethanol was completely abolished by intravenous injection of CGRP-(8-37). Indomethacin also inhibited the protective action of capsaicin, and this was accompanied by reduced levels of intragastric CGRP. Intragastric levels of prostaglandin E(2) were not increased by capsaicin treatment but those of 6-keto-prostaglandin F(1alpha), a metabolite of prostaglandin I(2), were markedly increased. No protective action of capsaicin was observed in IP(-/-) which lacked the ability to increase intragastric CGRP levels in response to ethanol containing capsaicin. The CGRP content of the stomach from untreated IP(-/-) did not differ from those in IP(+/+). Capsaicin (160 micro M) together with intragastric perfusion of beraprost sodium (PGI(2) analogue, 2.5 micro g/ml) showed enhanced protection against ethanol induced injury. This enhanced protection was completely blocked by intravenous injection of CGRP-(8-37).
  
  
  CONCLUSIONS
  The present results suggest that endogenous prostaglandin I(2) enhances the protective action of the capsaicin mediated neural emergency system against ethanol induced gastric mucosal injury through enhancement of CGRP release.
authors.affiliation: Department of Internal Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa 228-8555, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Arai
authors.forename: T
authors.initials: T
authors.lastname: Ohno
authors.forename: T
authors.initials: T
authors.lastname: Saeki
authors.forename: S
authors.initials: S
authors.lastname: Mizuguchi
authors.forename: K
authors.initials: K
authors.lastname: Kamata
authors.forename: I
authors.initials: I
authors.lastname: Hayashi
authors.forename: K
authors.initials: K
authors.lastname: Saigenji
authors.forename: T
authors.initials: T
authors.lastname: Murata
authors.forename: S
authors.initials: S
authors.lastname: Narumiya
authors.forename: M
authors.initials: M
authors.lastname: Majima
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000032:analysis / Q000378:metabolism*; D002211:Capsaicin / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000502:physiology*; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D007213:Indomethacin / Q000008:administration & dosage; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
chemical_list: D016861:Cyclooxygenase Inhibitors; D000431:Ethanol; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; D007213:Indomethacin