Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Japan.
Department of Pharmaceutical Sciences, Musashino University, Tokyo, Japan.
Br J Pharmacol. 2017 Oct;174(19):3370-3381. doi: 10.1111/bph.13960. Epub 2017 Aug 23.
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.
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.
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 receptor antagonist, ketanserin, suppressed butyrate-induced visceral hypersensitivity, whereas a selective dopamine D receptor antagonist, L-741626, did not. Furthermore, the 5-HT 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.
Our results indicate that chlorpromazine ameliorates visceral hypersensitivity and that the 5-HT receptor is a potential therapeutic target for treating abdominal pain and discomfort in IBS.
内脏敏感性是导致肠易激综合征（IBS）发病的原因。因此，预防内脏敏感性可以帮助避免 IBS 患者出现腹痛和不适。为了寻找治疗内脏敏感性的候选药物，我们筛选了现有药物预防大鼠结直肠扩张（CRD）诱导的内脏敏感性的能力，并发现氯丙嗪，一种典型的抗精神病药物，是一种候选化合物。在这项研究中，我们研究了氯丙嗪对内脏敏感性的影响。
使用压力测定仪通过测量腹部外斜肌收缩的电活动来监测内脏敏感性（内脏运动反应），以响应 CRD。在新生儿中通过结肠灌注丁酸钠或乙酸来诱导内脏敏感性。
氯丙嗪的口服给药抑制了丁酸钠诱导的对 CRD 的内脏敏感性。有趣的是，非典型抗精神病药物喹硫平和利培酮改善了丁酸钠诱导的内脏敏感性，而典型抗精神病药物氟哌啶醇和舒必利则没有。使用特定抑制剂的药理学分析表明，选择性 5-HT 受体拮抗剂酮色林抑制了丁酸钠诱导的内脏敏感性，而选择性多巴胺 D 受体拮抗剂 L-741626 则没有。此外，5-HT 受体激动剂 AL-34662 刺激了健康对照组大鼠的内脏对 CRD 的敏感性，但对丁酸钠处理的大鼠则没有。这些发现表明，结肠中 5-HT 水平的升高有助于诱导内脏敏感性。
我们的结果表明，氯丙嗪改善了内脏敏感性，5-HT 受体是治疗 IBS 患者腹痛和不适的潜在治疗靶点。
