title: Dopamine D₂-receptor antagonists ameliorate indomethacin-induced small intestinal ulceration in mice by activating α7 nicotinic acetylcholine receptors.
abstract: We have reported that nicotine and the specific α7AChR agonist ameliorate indomethacin-induced intestinal lesions in mice by activating α7 nicotinic acetylcholine receptors (α7nAChR). Dopamine D₂-receptor antagonists, such as domperidone and metoclopramide, enhance the release of ACh from vagal efferent nerves. The present study examined the effects of domperidone and metoclopramide on indomethacin-induced small intestinal ulceration in mice, focusing on the α7AChR. Male C57BL/6 mice were administered indomethacin (10 mg/kg, s.c.) and sacrificed 24 h later. Domperidone (0.1-10 mg/kg) and metoclopramide (0.03-0.3 mg/kg) were administered i.p. twice, at 0.5 h before and 8 h after indomethacin treatment, while methyllycaconitine (a selective antagonist of α7nAChR, 30 mg/kg) was administered twice, at 0.5 h before each domperidone treatment. Indomethacin caused severe hemorrhagic lesions in the small intestine, mostly to the jejunum and ileum, with a concomitant increase in myeloperoxidase (MPO) activity. Domperidone suppressed the severity of lesions and the increase in MPO activity at low doses (0.1-3 mg/kg), but not at a high dose (10 mg/kg). Similar effects were also observed by metoclopramide. The protective effects of domperidone and metoclopramide were totally abolished by prior administration of methyllycaconitine. Indomethacin treatment markedly enhanced inducible nitric oxide synthase and chemokine mRNA expression in the small intestine, but these responses were all significantly attenuated by either domperidone or metoclopramide. These findings suggest that dopamine D₂-receptor antagonists ameliorate indomethacin-induced small intestinal ulceration through the activation of endogenous anti-inflammatory pathways mediated by α7nAChR.
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yasuda
authors.forename: Ryoji
authors.initials: R
authors.lastname: Kawahara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hashimura
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamanaka
authors.forename: Maho
authors.initials: M
authors.lastname: Iimori
authors.forename: Kikuko
authors.initials: K
authors.lastname: Amagase
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kato
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000819:agonists / Q000037:antagonists & inhibitors / Q000633:toxicity; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004294:Domperidone / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D005765:Gastrointestinal Agents / Q000819:agonists / Q000037:antagonists & inhibitors / Q000633:toxicity; D005769:Gastrointestinal Motility / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007213:Indomethacin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000633:toxicity; D007410:Intestinal Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008787:Metoclopramide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018733:Nicotinic Antagonists / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D012720:Severity of Illness Index; D014456:Ulcer / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D005765:Gastrointestinal Agents; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D004294:Domperidone; D008787:Metoclopramide; D007213:Indomethacin