Identification of existing drugs effective for visceral pain relevant to irritable bowel syndrome through phenotypic screening in rats

[Speaker] Teita Asano:1
[Co-author] Mitsuko Takenaga:1
1:St. Marianna University School of Medicine, Japan

Background and Aims: Visceral hypersensitivity is responsible for pathogenesis of irritable bowel syndrome (IBS), especially abdominal pain. 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 pain sensitivity induced by colorectal distension (CRD) in rats.
Methods: We selected 209 clinically available drugs, including bronchodilators, anticonvulsants, antibiotics, anti-hypertensives and anti-allergy drugs for phenotypic screening. Visceromotor response (visceral pain) was monitored by measuring the electrical activity of the abdominal external oblique muscle contraction in response to CRD (10, 20, 40, 60 and 80 mmHg) in conscious rats using a barostat device. Stimulation of visceral sensitivity was induced by repeated noxious CRD (80 mmHg), a colonic instillation of sodium butyrate or trinitrobenzenesulfonic acid (TNBS), maternally separation, or dilute acetic acid instillation in neonates.
Results: From phenotypic screening, aminophylline and chlorpromazine were identified on the basis of its inhibition of visceral pain response to CRD, as well as the available clinical data of its tolerability. Aminophylline suppressed the stimulation of visceral pain in response to CRD induced by TNBS, maternally separation, and dilute acetic acid. This dose of aminophylline was similar to that required for its original pharmacological activity (bronchodilation). Other adenosine receptor antagonist, caffeine also significantly suppressed visceral pain to CRD in maternally separated rats. On the other hand, an antipsychotic drug chlorpromazine improved visceral hypersensitivity in butyrate-treated rats. Additionally, atypical antipsychotic drugs, quetiapine and risperidone also improved visceral hypersensitivity to CRD induced by sodium butyrate. Moreover, 5-HT2A receptor antagonist ketanserin rather than dopamine D2 receptor antagonist L-741,626 provided the attenuation of visceral pain response in butyrate-treated rats.
Conclusions: Taken together, our results suggest that the drugs target for adenosine receptors and 5-HT2A receptor could be beneficial for treatment of abdominal pain symptom in patients with IBS.

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