Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
Neurogastroenterol Motil. 2010 May;22(5):573-8, e124. doi: 10.1111/j.1365-2982.2009.01432.x. Epub 2009 Dec 9.
Irritable bowel syndrome (IBS) is associated with an enhanced perception to visceral stimuli and exaggerated stress response. The serotonergic neurotransmitter system has been strongly implicated as a key player in the manifestation of IBS symptomatology including visceral hypersensitivity. However the role of 5-HT(2B) receptors in visceral pain, although speculated, is currently unclear. Thus we assessed the impact of a selective 5-HT(2B) receptor antagonist, RS-127445, on visceral hypersensitivity in a model of brain gut axis dysfunction the Wistar Kyoto (WKY) rat.
Colorectal distension (CRD) was used to assess the visceral sensitivity of the WKY rat compared to normosensitive Sprague Dawley (SD) rats. Once we verified the visceral sensitivity of the WKY rat we assessed the efficacy of RS-127445 in pain signalling from the colorectum. We administered the compound peripherally (i.p.) and centrally (i.c.v.) in order to ascertain the site of action of RS 127445. Behavioural responses to colorectal distention were then monitored.
The WKY rats were more viscerally hypersensitive than the SD as previously shown. RS-127445 (5 mg kg(-1), i.p.) significantly reversed visceral hypersensitivity in WKY animals. Moreover, when administered intracerebroventricularly RS-127445 (100 nM) also decreased the number of pain behaviours during noxious CRD in the WKY animals.
CONCLUSIONS & INFERENCES: Taken together, blockade of 5-HT(2B) receptors offers an exciting novel therapeutic target for pain relief in stress-related gastrointestinal disorders such as IBS.
肠易激综合征（IBS）与内脏刺激的感知增强和应激反应过度有关。5-羟色胺能神经递质系统被强烈认为是 IBS 症状表现的关键因素，包括内脏敏感性。然而，5-HT2B 受体在内脏疼痛中的作用，尽管推测存在，但目前尚不清楚。因此，我们评估了选择性 5-HT2B 受体拮抗剂 RS-127445 对脑肠轴功能障碍模型中 Wistar Kyoto（WKY）大鼠内脏敏感性的影响。
采用结肠扩张（CRD）评估 WKY 大鼠与正常敏感 Sprague Dawley（SD）大鼠的内脏敏感性。在验证了 WKY 大鼠的内脏敏感性后，我们评估了 RS-127445 对来自结肠的疼痛信号的疗效。我们通过外周（ip）和中枢（icv）给药来确定 RS 127445 的作用部位。然后监测对结肠扩张的行为反应。
正如之前所示，WKY 大鼠比 SD 大鼠更具有内脏敏感性。RS-127445（5mgkg-1，ip）显著逆转了 WKY 动物的内脏敏感性。此外，当给予脑室内 RS-127445（100nM）时，也减少了 WKY 动物在有害性 CRD 期间的疼痛行为次数。
总之，5-HT2B 受体阻断为应激相关胃肠道疾病（如 IBS）的疼痛缓解提供了一个令人兴奋的新治疗靶点。
