Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, H-7624 Pécs, Szigeti u. 12., Hungary.
Eur J Pain. 2010 Apr;14(4):351-8. doi: 10.1016/j.ejpain.2009.07.005. Epub 2009 Aug 15.
Protease-activated receptor-2 (PAR-2) is a G-protein-coupled receptor activated through proteolytic cleavage. It is localized on epithelial, endothelial and inflammatory cells, as well as on transient receptor potential vanilloid 1 (TRPV1) receptor-expressing neurones. It plays an important role in inflammatory/nociceptive processes. Since there are few reports concerning PAR-2 function in joints, the effects of intraarticular PAR-2 activation on joint pain and inflammation were studied. Secondary hyperalgesia/allodynia, spontaneous weight distribution, swelling and inflammatory cytokine production were measured and the involvement of TRPV1 ion channels was investigated in rats and mice. Injection of the PAR-2 receptor agonist SLIGRL-NH(2) into the knee decreased touch sensitivity and weight bearing of the ipsilateral hindlimb in both species. Secondary mechanical allodynia/hyperalgesia and impaired weight distribution were significantly reduced by the TRPV1 antagonist SB366791 in rats and by the genetic deletion of this receptor in mice. PAR-2 activation did not cause significant joint swelling, but increased IL-1beta concentration which was not influenced by the lack of the TRPV1 channel. For comparison, intraplantar SLIGRL-NH(2) evoked similar primary mechanical hyperalgesia and impaired weight distribution in both WT and TRPV1 deficient mice, but oedema was smaller in the knockouts. The inactive peptide, LRGILS-NH(2), injected into either site did not induce any inflammatory or nociceptive changes. These data provide evidence for a significant role of TRPV1 receptors in secondary mechanical hyperalgesia/allodynia and spontaneous pain induced by PAR-2 receptor activation in the knee joint. Although intraplantar PAR-2 activation-induced oedema is also TRPV1 receptor-mediated, primary mechanical hyperalgesia, impaired weight distribution and IL-1beta production are independent of this channel.
蛋白酶激活受体 2 (PAR-2) 是一种 G 蛋白偶联受体，通过蛋白水解切割而被激活。它定位于上皮细胞、内皮细胞和炎症细胞，以及表达瞬时受体电位香草酸 1 (TRPV1) 受体的神经元上。它在炎症/伤害感受过程中发挥重要作用。由于关于 PAR-2 在关节中的功能的报道很少，因此研究了关节内 PAR-2 激活对关节疼痛和炎症的影响。在大鼠和小鼠中测量了继发性痛觉过敏/感觉异常、自发性体重分布、肿胀和炎性细胞因子产生，并研究了 TRPV1 离子通道的参与。将 PAR-2 受体激动剂 SLIGRL-NH(2) 注射到膝关节中，降低了两种物种对侧后肢的触敏性和负重能力。在大鼠中，TRPV1 拮抗剂 SB366791 显著减少了继发性机械性感觉异常/痛觉过敏和体重分布受损，而在小鼠中，该受体的基因缺失也降低了这种作用。PAR-2 激活不会导致明显的关节肿胀，但会增加 IL-1beta 浓度，而缺乏 TRPV1 通道对其没有影响。相比之下，足底注射 SLIGRL-NH(2) 在 WT 和 TRPV1 缺陷型小鼠中均引起类似的原发性机械性痛觉过敏和体重分布受损，但在敲除小鼠中肿胀较小。在两种动物中，将无活性肽 LRGILS-NH(2) 注射到任一部位均不会引起任何炎症或伤害感受变化。这些数据为 TRPV1 受体在膝关节中 PAR-2 受体激活引起的继发性机械性痛觉过敏/感觉异常和自发性疼痛中发挥重要作用提供了证据。尽管足底 PAR-2 激活引起的水肿也是 TRPV1 受体介导的，但原发性机械性痛觉过敏、体重分布受损和 IL-1beta 产生与该通道无关。
