Dual Alpha 2C /5HT 1A Receptor Agonist Allyphenyline Induces Gastroprotection and Inhibits Fundic and Colonic Contractility

Abstract

Background

Allyphenyline, a novel α₂-adrenoceptor (AR) ligand, has been shown to selectively activate α_2C-adrenoceptors (AR) and 5HT_1A receptors, but also to behave as a neutral antagonist of α_2A-ARs. We exploited this unique pharmacological profile to analyze the role of α_2C-ARs and 5HT_1A receptors in the regulation of gastric mucosal integrity and gastrointestinal motility.

Methods

Gastric injury was induced by acidified ethanol in Wistar rats. Mucosal catalase and superoxide dismutase levels were measured by assay kits. The effect of allyphenyline on electrical field stimulation (EFS)-induced fundic and colonic contractions was determined in C57BL/6 mice.

Results

Intracerebroventricularly injected allyphenyline (3 and 15 nmol/rat) dose dependently inhibited the development of mucosal damage, which was antagonized by ARC 239 (α_2B/C-AR and 5HT_1A receptor antagonist), (S)-WAY 100135 (selective 5HT_1A receptor antagonist), and JP-1302 (selective α_2C-AR antagonist). This protection was accompanied by significant elevation of mucosal catalase and superoxide dismutase levels. Allyphenyline (10⁻⁹–10⁻⁵ M) also inhibited EFS-induced fundic contractions, which was antagonized by ARC 239 and (S)-WAY 100135, but not by JP-1302. Similar inhibition was observed in the colon; however, in this case only ARC 239 reduced this effect, while neither selective inhibition of α_2C-ARs and 5HT_1A receptors nor genetic deletion of α_2A- and α_2B-ARs influenced it.

Conclusions

Activation of both central α_2C-ARs and 5HT_1A receptors contributes to the gastroprotective action of allyphenyline in rats. Its inhibitory effect on fundic contractions is mediated by 5HT_1A receptors, but neither α₂-ARs nor 5HT_1A receptors take part in its inhibitory effect on colonic contractility in mice.

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