title: Facilitation by endogenous prostaglandins of capsaicin-induced gastric protection in rodents through EP2 and IP receptors.
abstract: We investigated the role that prostaglandins (PGs) and EP receptors play in facilitating the gastroprotective action of capsaicin against HCl/ethanol in rats and mice. Male Sprague-Dawley rats and C57BL/6 mice were used after 18 h of fasting. The animals were given HCl/ethanol (60% in 150 mM HCl) p.o. and killed 1 h later. Capsaicin or various EP agonists were given p.o. 30 min or i.v. 10 min before HCl/ethanol. In some cases, indomethacin or various EP agonists were given s.c. 30 min or i.v 10 min before capsaicin, respectively. Gastric lesions induced by HCl/ethanol were significantly inhibited by PGE(2) as well as capsaicin. The effect of PGE(2) was antagonized by ONO-AE-829 (EP1 antagonist), whereas the capsaicin action was mitigated by indomethacin as well as sensory deafferentation but not by ONO-AE-829. The generation of mucosal PGE(2) was not affected by either capsaicin or sensory deafferentation, but was significantly inhibited by indomethacin. Although neither butaprost (EP2), ONO-NT-012 (EP3), nor 11-deoxy PGE1 (EP4) alone had any effect on HCl/ethanol-induced gastric lesions, only butaprost restored the protective action of capsaicin in the presence of indomethacin. Capsaicin provided a protective action against HCl/ethanol-induced gastric lesions in wild-type (+/+) mice in an indomethacin-sensitive manner, and this action was similarly observed in EP1 (-/-) and EP3 (-/-) mice but not in the animals lacking IP receptors. These results suggest that capsaicin exhibits gastric cytoprotection, essentially by stimulating sensory neurons, and this action is facilitated by endogenous PGs through EP2/IP receptors, probably sensitizing the sensory neurons to capsaicin.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan. takeuchi@mb.kyoto-phu.ac.jp
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kato
authors.forename: Masanori
authors.initials: M
authors.lastname: Takeeda
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Masato
authors.initials: M
authors.lastname: Nakashima
authors.forename: Masahiro
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002211:Capsaicin / Q000627:therapeutic use*; D019610:Cytoprotection / Q000187:drug effects; D004064:Digestive System / Q000187:drug effects / Q000293:injuries; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D000431:Ethanol; D005753:Gastric Mucosa / Q000187:drug effects / Q000502:physiology; D006851:Hydrochloric Acid; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011453:Prostaglandins / Q000378:metabolism*; D020011:Protective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D012039:Regional Blood Flow / Q000187:drug effects; D013272:Stomach Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011453:Prostaglandins; D020011:Protective Agents; C545645:Ptger2 protein, mouse; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D000431:Ethanol; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; C043867:cicaprost; D006851:Hydrochloric Acid; D002211:Capsaicin; D007213:Indomethacin