The 5-HT4 receptor agonist mosapride attenuates NSAID-induced gastric mucosal damage.
BACKGROUND
The cholinergic anti-inflammatory pathway is a novel physiological mechanism found at various locations in the body where the nicotinic regulation of inflammatory cells through the autonomic nervous system is involved. In this study, we tested the hypothesis that cholinergic nerve stimulation by a 5-HT(4) agonist may modulate the progression of gastric mucosal ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs).


METHODS
Acute gastric ulcers were induced in rats by the oral administration of indomethacin.


RESULTS
Gastric damage analysis indicated that pretreatment with mosapride, a selective 5-HT(4) agonist, at 0.25, 0.5, and 0.75 mg/kg, inhibited the mucosal damage induced by indomethacin. In gastric emptying analysis, an evacuation effect was observed in the 3.0 mg/kg mosapride pretreatment group, but this effect was not observed in the lower dose (0.5 mg/kg) group. The antiulcerogenic activity of mosapride treatment (at 0.5 mg/kg) was blocked by a 5-HT(4)-specific antagonist, GR113808 (1 mg/kg, i.v.). Additionally, we demonstrated that methyllycaconitine (0.29 and 0.87 mg/kg i.p.), a selective inhibitor of alpha7 nicotinic acetylcholine (ACh) receptors (alpha7nAChRs), ablated the antiulcerogenic action of mosapride.


CONCLUSIONS
These results suggest that the mucosal protective action of mosapride may be mediated by an action on immune cells through the acceleration of ACh release from parasympathetic nerves via the activation of 5-HT(4) receptors, followed by activation of the nicotinic anti-inflammatory system. It appears that the alpha7nAChR may be involved in the antiulcerogenic action of mosapride.
Fujisawa
Masahiko
M
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan.
Murata
Takahisa
T
Hori
Masatoshi
M
Ozaki
Hiroshi
H
D000109:Acetylcholine / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D007213:Indomethacin / Q000009:adverse effects; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D013276:Stomach Ulcer / Q000139:chemically induced / Q000517:prevention & control*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; C579165:Chrna7 protein, rat; D009025:Morpholines; D011978:Receptors, Nicotinic; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists; D064569:alpha7 Nicotinic Acetylcholine Receptor; C062720:mosapride; D000109:Acetylcholine; D007213:Indomethacin