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

Pharmacol Res. 2012 Sep;66(3):226-34. doi: 10.1016/j.phrs.2012.06.002. Epub 2012 Jun 12.


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.

MeSH terms

  • Aconitine / analogs & derivatives
  • Aconitine / pharmacology
  • Animals
  • Anti-Ulcer Agents / pharmacology
  • Benzamides / pharmacology
  • Fenclonine / pharmacology
  • Indoles / pharmacology
  • Indomethacin
  • Intestinal Diseases / chemically induced
  • Intestinal Diseases / drug therapy
  • Intestinal Diseases / metabolism*
  • Intestinal Diseases / pathology
  • Intestine, Small / drug effects
  • Intestine, Small / metabolism*
  • Intestine, Small / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Morpholines / pharmacology
  • Ondansetron / pharmacology
  • Receptors, Nicotinic / metabolism
  • Receptors, Serotonin / metabolism
  • Receptors, Serotonin, 5-HT3 / metabolism*
  • Receptors, Serotonin, 5-HT4 / metabolism*
  • Serotonin / metabolism*
  • Serotonin Antagonists / pharmacology
  • Serotonin Receptor Agonists / pharmacology
  • Sulfonamides / pharmacology
  • Ulcer / chemically induced
  • Ulcer / drug therapy
  • Ulcer / metabolism
  • Ulcer / pathology*
  • alpha7 Nicotinic Acetylcholine Receptor


  • Anti-Ulcer Agents
  • Benzamides
  • Chrna7 protein, mouse
  • Indoles
  • Morpholines
  • Receptors, Nicotinic
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT3
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Sulfonamides
  • alpha7 Nicotinic Acetylcholine Receptor
  • Receptors, Serotonin, 5-HT4
  • methyllycaconitine
  • Serotonin
  • Ondansetron
  • mosapride
  • Fenclonine
  • Aconitine
  • Indomethacin
  • GR 113808