Ameliorative effect of chlorpromazine hydrochloride on visceral hypersensitivity in rats: possible involvement of 5-HT_2A receptor.

BACKGROUND AND PURPOSE:Visceral hypersensitivity is responsible for pathogenesis of irritable bowel syndrome (IBS). Therefore, its prevention can help avoid abdominal pain and discomfort in IBS. To find candidate drugs for visceral hypersensitivity, we screened existing medicines for their ability to prevent visceral sensitivity induced by colorectal distension (CRD) in rats and identified chlorpromazine, a typical antipsychotic drug, as a candidate compound. In this study, we investigated the effect of chlorpromazine on visceral hypersensitivity. EXPERIMENTAL APPROACH:Visceral sensitivity (visceromotor response) was monitored by measuring the electrical activity of the abdominal external oblique muscle contraction in response to CRD using a barostat apparatus. Visceral hypersensitivity was induced by a colonic instillation of sodium butyrate or acetic acid in neonates. KEY RESULTS:Oral administration of chlorpromazine suppressed butyrate-induced visceral hypersensitivity to CRD. Interestingly, atypical antipsychotic drugs, quetiapine and risperidone, ameliorated butyrate-induced visceral hypersensitivity, whereas the typical antipsychotic drugs, haloperidol and sulpiride, did not. Pharmacological analysis using specific inhibitors showed that a selective 5-HT_2A receptor antagonist, ketanserin, suppressed butyrate-induced visceral hypersensitivity, whereas a selective dopamine D₂ receptor antagonist, L-741626, did not. Furthermore, the 5-HT_2A receptor agonist AL-34662 stimulated visceral sensitivity to CRD in healthy control rats but not in butyrate-treated rats. These findings suggest that increased 5-HT levels in the colon contribute to the induction of visceral hypersensitivity. CONCLUSIONS AND IMPLICATIONS:Our results indicate that chlorpromazine ameliorates visceral hypersensitivity and that the 5-HT_2A receptor is a potential therapeutic target for treating abdominal pain and discomfort in IBS.

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