CRF在大鼠5-HT信号通路和内脏高敏感中的作用

Role of CRF on 5-HT Signaling Pathway and Visceral Hypersensitivity in Rats

背景:肠易激综合征(IBS)是一种常见的胃肠功能紊乱性疾病,内脏高敏感为其重要生物学指标。5-羟色胺(5-HT)信号通路在介导外周和中枢内脏感觉的传递中发挥重要作用,且与促肾上腺皮质激素释放因子(CRF)关系密切。目的:研究CRF及其不同受体亚型对内脏高敏感大鼠5-HT信号通路的调控作用,探讨IBS内脏高敏感的可能机制。方法:60只Sprague-Dawley大鼠随机分为空白对照组、内脏高敏感模型组、干预对照组、干预一组和干预二组,每组12只。三组干预组大鼠分别于造模前1d侧脑室注射0.9%NaCl溶液、CRF-R1拮抗剂和CRF-R2激动剂。腹部收缩反射(AWR)试验评估大鼠内脏敏感性,免疫组化法检测大鼠脑、脊髓、结肠组织5-HT表达。结果:模型组和干预对照组内脏敏感性显著高于空白对照组,干预一组和干预二组显著低于干预对照组(P<0.05)。模型组和干预对照组脑组织5-HT表达显著低于空白对照组,脊髓后角和结肠组织5-HT表达显著高于空白对照组(P<0.05);干预一组和干预二组脑组织5-HT表达较干预对照组显著上调,脊髓后角和结肠组织5-HT表达较干预对照组显著下调(P<0.05)。结论:中枢CRF-R1抑制或CRF-R2激活可改变内脏高敏感大鼠脑-肠轴不同部位的5-HT表达,证实CRF对5-HT信号通路具有调控作用,可能是引起IBS内脏高敏感的机制之一。

Irritable bowel syndrome （IBS） is a common functional gastrointestinal disorder, and visceral hypersensitivity is the key biological parameter of IBS. 5-Hydroxytryptamine （5-HT） signaling pathway plays an important role in mediating both the peripheral and central visceral sensory transmission and has a close relationship with corticotropin-releasing factor （CRF）. Aims： To study the regulatory role of CRF and its receptors on 5-HT signaling pathway in visceral hypersensitivity rats, so as to explore the possible mechanism of visceral hypersensitivity in IBS. Methods＂ Sixty Sprague-Dawley rats were randomly assigned into control group, visceral hypersensitivity model group, sham-intervention group, intervention group 1 and intervention group 2, with 12 rats in each group. The rats in shamintervention group, intervention group 1 and intervention group 2 were lateral ventricle injected with normal saline, CRF- R1 antagonist and CRF-R2 agonist 1 day before establishing the model, respectively. Visceral sensitivity was assessed by abdominal withdrawal reflex （AWR） test, and the expression of 5-HT in brain, spinal cord and colon was determined by immunohistoehemistry. Results： Visceral sensitivity was significantly higher in model group and sham-intervention group than that in control group, while that in intervention group 1 and 2 was significantly lower than that in sham-intervention group （P〈0.05）. Expression of 5-HT in brain in model group and sham-intervention group was significantly lower than that in control group, while that in spinal dorsal horn and colon was significantly higher than that in control group （P〈0.05）. Expression of 5-HT in brain in intervention group 1 and 2 was significantly increased compared to sham-intervention group, while that in spinal dorsal horn and colon was significantly decreased （P〈0.05）. Conclusions： Central inhibition of CRF-R1 or activation of CRF-R2 can alter the expression of 5-HT in different site of the brain-gut axis of rats with visceral hypersensitivity, which verify the regulatory role of CRF on 5-HT signaling pathway, and it might be one of the possible mechanism of visceral hypersensitivity in IBS.