Dual role of serotonin in the pathogenesis of indomethacin-induced small intestinal ulceration: pro-ulcerogenic action via 5-HT3 receptors and anti-ulcerogenic action via 5-HT4 receptors.
Serotonin (5-HT) exerts multiple physiological functions not only in the central and peripheral nervous systems but also in the gastrointestinal tract, and these multiple functions are accounted for by a variety of 5-HT receptor subtypes. We investigated the role of 5-HT in the pathogenesis of indomethacin-induced intestinal lesions in mice, in relation to 5-HT receptor subtypes. A single oral administration of indomethacin (10 mg/kg) provoked damage in the small intestine of mice 24 h later, and this response was prevented by pretreatment with p-chlorophenylalanine (a 5-HT synthesis inhibitor). The administration of 5-HT3 receptor antagonists, such as ondansetron and ramosetron, dose-dependently reduced the severity of the intestinal lesions, whereas a high dose of GR113808 (a 5-HT4 receptor antagonist) significantly aggravated these lesions. In contrast, NAN-190 (a 5-HT1 receptor antagonist), ketanserin (a 5-HT2 receptor antagonist), and SB269970 (a 5-HT7 receptor antagonist) had no effect on these lesions. Mosapride (a 5-HT4 receptor agonist) significantly reduced the severity of indomethacin-induced intestinal lesions, and this protective effect was totally prevented by either GR113808 or methyllycaconitine (an α7-nicotinic acetylcholine receptor antagonist). Indomethacin increased the activity of myeloperoxidase and the expression of inducible nitric oxide synthase, inflammatory cytokines, and chemokines in the small intestine; these responses were significantly attenuated by ondansetron and mosapride. These findings suggest that endogenous 5-HT exerts a dual role in the pathogenesis of indomethacin-induced intestinal lesions: pro-ulcerogenic action via 5-HT3 receptors and anti-ulcerogenic action via 5-HT4 receptors, and the latter effect via 5-HT4 receptors may be mediated by activation of α7-nicotinic acetylcholine receptors.
Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto, Japan. skato@mb.kyoto-phu.ac.jp
Shinichi
S
Kato
Narumi
N
Matsuda
Kenjiro
K
Matsumoto
Mai
M
Wada
Naoki
N
Onimaru
Masashi
M
Yasuda
Kikuko
K
Amagase
Syunji
S
Horie
Koji
K
Takeuchi
D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D010134:Fenclonine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin; D007410:Intestinal Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D017294:Ondansetron / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014456:Ulcer / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D000897:Anti-Ulcer Agents; D001549:Benzamides; C579166:Chrna7 protein, mouse; D007211:Indoles; D009025:Morpholines; D011978:Receptors, Nicotinic; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D064569:alpha7 Nicotinic Acetylcholine Receptor; D044422:Receptors, Serotonin, 5-HT4; C054634:methyllycaconitine; D012701:Serotonin; D017294:Ondansetron; C062720:mosapride; D010134:Fenclonine; D000157:Aconitine; D007213:Indomethacin; C082871:GR 113808