Department of Regional Medicine and Education, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan; Center for Medical Education, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
Eur J Pharmacol. 2020 Nov 15;887:173565. doi: 10.1016/j.ejphar.2020.173565. Epub 2020 Sep 15.
An impaired gut barrier, possibly leading to visceral hypersensitivity has been recently recognized to be one of the pivotal pathophysiology of irritable bowel syndrome (IBS). We previously showed that lipopolysaccharide (LPS), corticotropin-releasing factor (CRF), and repeated water avoidance stress (WAS) induce visceral hypersensitivity and colonic hyperpermeability via pro-inflammatory cytokine signaling (rat IBS models). Although the precise mechanisms of action are unclear, imipramine, a tricyclic antidepressant, improves IBS symptoms, and also has anticytokine properties. In this study, we hypothesized that imipramine improves the gut barrier to ameliorate IBS symptoms. To test this hypothesis, we determined its effects on visceral hypersensitivity and colonic hyperpermeability in rat IBS models. The visceral pain threshold in response to colonic balloon distention was electrophysiologically estimated by abdominal muscle contractions, and colonic permeability was measured by quantifying the absorbed Evans blue in colonic tissue in vivo. Subcutaneous imipramine injection (7, 20, 50 mg/kg) dose-dependently inhibited LPS-induced (1 mg/kg, subcutaneously) visceral hypersensitivity and colonic hyperpermeability. Imipramine also blocked these gastrointestinal (GI) changes induced by CRF (50 μg/kg, intraperitoneally) or repeated WAS (1 h daily for 3 days). Yohimbine (an α-adrenoceptors antagonist), sulpiride (a dopamine D receptor antagonist), and naloxone hydrochloride (an opioid receptor antagonist) reversed these effects of imipramine in the LPS model. Therefore, imipramine may block GI changes in IBS via α-adrenoceptors, dopamine D, and opioid signaling. The improvement in the gut barrier resulting in inhibition of visceral pain is considered a valid mechanism of imipramine to ameliorate IBS symptoms.
肠道屏障受损，可能导致内脏高敏感，最近被认为是肠易激综合征 (IBS) 的关键病理生理学之一。我们之前的研究表明，脂多糖 (LPS)、促肾上腺皮质释放因子 (CRF) 和反复水回避应激 (WAS) 通过促炎细胞因子信号转导诱导内脏高敏感和结肠高通透性（大鼠 IBS 模型）。尽管确切的作用机制尚不清楚，但三环类抗抑郁药丙咪嗪可改善 IBS 症状，且具有抗细胞因子特性。在这项研究中，我们假设丙咪嗪可改善肠道屏障，从而改善 IBS 症状。为了验证这一假设，我们在大鼠 IBS 模型中确定了它对内脏高敏感和结肠高通透性的影响。通过腹部肌肉收缩，电生理评估对结肠球囊扩张的内脏疼痛阈值，通过体内定量测量结肠组织中吸收的 Evans 蓝来测量结肠通透性。皮下注射丙咪嗪（7、20、50mg/kg）剂量依赖性地抑制 LPS（1mg/kg，皮下注射）诱导的内脏高敏感和结肠高通透性。丙咪嗪还阻断了 CRF（50μg/kg，腹腔内注射）或反复 WAS（每天 1 小时，连续 3 天）引起的这些胃肠道 (GI) 变化。育亨宾（α-肾上腺素能受体拮抗剂）、舒必利（多巴胺 D 受体拮抗剂）和盐酸纳洛酮（阿片受体拮抗剂）逆转了 LPS 模型中丙咪嗪的这些作用。因此，丙咪嗪可能通过 α-肾上腺素能受体、多巴胺 D 和阿片受体信号通路阻断 IBS 中的 GI 变化。改善肠道屏障，从而抑制内脏疼痛，被认为是丙咪嗪改善 IBS 症状的有效机制。
