Greenwood-Van Meerveld B, Johnson A C, Cochrane S, Schulkin J, Myers D A
Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Neurogastroenterol Motil. 2005 Jun;17(3):415-22. doi: 10.1111/j.1365-2982.2005.00648.x.
The potential relationship between stress and irritable bowel syndrome (IBS) symptomatology suggests a possible role for stress-mediating hormones, such as corticotropin-releasing factor (CRF), in the altered perception of stimuli in IBS patients. In previous studies, Wistar-Kyoto (WKY) rats with genetic indices of high anxiety demonstrated colonic hypersensitivity coupled with a high basal level of CRF within the central nervous system. In the current study we tested the hypothesis that a selective, non-peptide CRF1 receptor antagonist, antalarmin, would inhibit hypersensitivity in the WKY rat colon. Colonic sensitivity was determined by monitoring a visceromotor behavioural response during innocuous levels of colorectal distention (30 mmHg). In high anxiety WKY rats we found that antalarmin (20 mg kg-1, i.p.) significantly decreased the visceromotor response induced by colorectal distention. In a second study central administration (i.c.v.) of CRF was used to induce colonic hypersensitivity in lower anxiety Fischer 344 (F-344) rats, and in this model, antalarmin significantly inhibited the CRF-induced colonic hypersensitivity. In summary, a selective CRF1 receptor antagonist, antalarmin, inhibits colonic hypersensitivity apparent in WKY rats or in F-344 rats given a central administration of CRF. Our findings suggest that CRF1 receptor antagonism may represent a novel therapeutic approach for the treatment of IBS.
压力与肠易激综合征（IBS）症状之间的潜在关系表明，诸如促肾上腺皮质激素释放因子（CRF）等压力调节激素在IBS患者对刺激的感知改变中可能发挥作用。在先前的研究中，具有高焦虑遗传指标的Wistar-Kyoto（WKY）大鼠表现出结肠超敏反应，同时中枢神经系统内CRF的基础水平较高。在本研究中，我们测试了一种选择性非肽CRF1受体拮抗剂安他拉明会抑制WKY大鼠结肠超敏反应的假设。通过监测在无害水平的结肠扩张（30 mmHg）期间的内脏运动行为反应来确定结肠敏感性。在高焦虑的WKY大鼠中，我们发现安他拉明（20 mg kg-1，腹腔注射）显著降低了结肠扩张诱导的内脏运动反应。在第二项研究中，对低焦虑的Fischer 344（F-344）大鼠进行中枢给药（脑室内）CRF以诱导结肠超敏反应，在该模型中，安他拉明显著抑制了CRF诱导的结肠超敏反应。总之，选择性CRF1受体拮抗剂安他拉明可抑制WKY大鼠或接受中枢给药CRF的F-344大鼠中明显的结肠超敏反应。我们的研究结果表明，CRF1受体拮抗作用可能代表一种治疗IBS的新方法。
