Bradesi S
Center for Neurobiology of Stress, University of California Los Angeles, Division of Digestive Diseases, Los Angeles, CA 90073, USA.
Neurogastroenterol Motil. 2009 Nov;21(11):1129-32. doi: 10.1111/j.1365-2982.2009.01373.x.
Protease-activated receptors (PARs) are a family of G-protein-coupled receptors with a widespread distribution that are involved in various physiological functions including inflammation and nociception. In a recent study in Neurogastroenterology and Motility, Augé et al. describe for the first time the presence of PAR4 on visceral primary afferent neurons and its role in modulating colonic nociceptive responses, colonic hypersensitivity and primary afferent responses to PAR2 and Transient Receptor Potential Vanilloid-4 (TRPV4). Using the model of visceromotor response (VMR) to colorectal distension (CRD), they show that a PAR4 agonist delivered into the colon lumen decreases basal visceral response to CRD and reduces the exacerbated VMR to CRD induced by treatment with PAR2 or TRPV4 agonists. In isolated sensory neurons, they show that a PAR4 agonist inhibits calcium mobilization induced by PAR2 or TRPV4 agonists. Finally, they describe increased pain behaviour evoked by luminal application of mustard oil in PAR4 deficient mice compared to wild type controls. The newly discovered role of PAR4 in modulating visceral pain adds to our growing understanding of the contribution of colonic proteases and PARs to the mechanisms involved in colonic hypersensitivity and their potential role as therapeutic targets for irritable bowel syndrome.
蛋白酶激活受体（PARs）是一类广泛分布的G蛋白偶联受体，参与包括炎症和伤害感受在内的多种生理功能。在最近发表于《神经胃肠病学与动力》杂志的一项研究中，奥热等人首次描述了PAR4在内脏初级传入神经元上的存在及其在调节结肠伤害性反应、结肠超敏反应以及初级传入神经元对PAR2和瞬时受体电位香草酸亚型4（TRPV4）反应中的作用。利用对结直肠扩张（CRD）的内脏运动反应（VMR）模型，他们发现将PAR4激动剂注入结肠腔可降低对CRD的基础内脏反应，并减轻由PAR2或TRPV4激动剂治疗诱导的对CRD加剧的VMR。在分离的感觉神经元中，他们发现PAR4激动剂可抑制PAR2或TRPV4激动剂诱导的钙动员。最后，他们描述了与野生型对照相比，PAR4基因敲除小鼠经腔内应用芥子油后诱发的疼痛行为增加。PAR4在调节内脏疼痛方面新发现的作用，加深了我们对结肠蛋白酶和PARs在结肠超敏反应机制中的作用以及它们作为肠易激综合征治疗靶点潜在作用的理解。
