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Chlorpromazine hydrochloride suppresses visceral hypersensitivity to colorectal distension in a rat model of irritable bowel syndrome
Author(s) -
Asano Teita,
Takenaga Mistuko
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.666.6
Subject(s) - medicine , irritable bowel syndrome , visceral pain , chlorpromazine , pharmacology , abdominal pain , gastroenterology , anesthesia , nociception , receptor
Background and Aims Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by chronic and recurrent abdominal pain and discomfort associated with altered bowel habits. Although IBS markedly reduces the patient's quality of life, pharmacological therapy has not been established. Visceral hypersensitivity plays an important role in pathogenesis of IBS. In the present study, we screened a compound library consisting of clinically used drugs for their ability to prevent visceral hypersensitivity to colorectal distension (CRD) in rats. Methods Visceral sensitivity was monitored by the measurement of the electrical activity of the abdominal external oblique muscle in response to CRD (visceromotor response) in rats using a pressure‐volume control device, barostat. Two hundred nine clinically used drugs including bronchodilators, anticonvulsants, antibiotics, anti‐hypertensives and anti‐allergy drugs were selected for drug screen in rats. The drugs were screened for their ability to suppress visceral sensitivity to repeated CRD. Visceral hypersensitivity to CRD was induced by intra‐colonic administration of sodium butyrate in adulthood or 0.5% acetic acid administration in the early neonatal period. Results Chlorpromazine, a typical antipsychotic drug, was identified as a compound that is able to suppress the visceromotor response to repetitive CRD. Oral administration of a 4 mg/kg of chlorpromazine restored visceral hypersensitivity to CRD induced by sodium butyrate or acetic acid to normal condition. This dose of chlorpromazine did not affect visceral sensitivity to CRD and colonic compliance in non‐stressed rats. We also found that quetiapine and risperidone (atyptical psychotic drugs) but not sulpiride and haloperidol (other typical psychotics drugs) suppressed butyrate‐induced colonic hypersensitivity. Chlorpromazine has antagonist action at dopamine D2 receptors and serotonin 2A (5‐HT2A) receptors. From analysis with selective antagonists, kentanserin (a 5‐HT2A receptor antagonist) but not L‐741,626 (a dopamine D2 receptor antagonist) suppressed colonic hypersensitivity induced by butyrate. Furthermore, a peripherally active 5‐HT2A agonist, AL‐34662 produced colonic hypersensitivity in normal rats. Conclusions Taken together, our results suggest that chlorpromazine ameliorates visceral hypersensitivity to CRD through the inhibition of 5‐HT2A receptors. Then, the activation of 5‐HT2A receptors may be involved in the development of visceral hypersensitivity. 5‐HT2A receptors could be a molecular target for IBS treatment. Support or Funding Information This research received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors.