Martin Laurence, Augé Céline, Boué Jérôme, Buresi Michelle C, Chapman Kevin, Asfaha Samuel, Andrade-Gordon Patricia, Steinhoff Martin, Cenac Nicolas, Dietrich Gilles, Vergnolle Nathalie
INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, F-31000 Toulouse, France.
Pain. 2009 Nov;146(1-2):121-9. doi: 10.1016/j.pain.2009.07.016. Epub 2009 Aug 11.
Serine proteases such as thrombin, trypsin and mast cell tryptase can act on different cell types through protease-activated receptors (PARs). These receptors have been shown to be implicated in several phenomena such as inflammation, platelet activation, immune response and atherosclerosis. Several studies recently reported PARs expression on neurons and some of them demonstrated that these receptors could interfere with nociception. The contribution of PAR(1) to inflammatory pain and the mechanism involved in this phenomenon were investigated. Intraplantar injection of PAR(1) agonist increased withdrawal latency and reduced response frequency to von Frey filaments, thus inhibiting nociceptive response to both mechanical and thermal stimuli in mice. PAR(1) agonist also reduced carrageenan-induced inflammatory hyperalgesia. The anti-nociceptive effects of PAR(1) agonist were mediated by endogenous opioids, as this effect was inhibited by local injection of naloxone methiodide, and because intraplantar injection of PAR(1) agonist increased mRNA expression of the endogenous opioid precursor proenkephalin. However, PAR(1) agonist was not able to inhibit calcium signals in isolated sensory neurons exposed to pro-nociceptive agents. Finally, despite similar inflammatory parameters, PAR(1)-deficient mice showed a strong potentiation of inflammatory hyperalgesia induced by the intraplantar injection of either formalin or carrageenan, or in the chronic model of collagen-induced arthritis, compared to wild-type mice. This study highlights a previously unknown endogenous mechanism of analgesia, showing a central role for the thrombin receptor PAR(1) in the regulation of inflammatory pain and as an activator of opioid pathways.
凝血酶、胰蛋白酶和肥大细胞类胰蛋白酶等丝氨酸蛋白酶可通过蛋白酶激活受体（PARs）作用于不同的细胞类型。这些受体已被证明与多种现象有关，如炎症、血小板活化、免疫反应和动脉粥样硬化。最近有几项研究报道了PARs在神经元上的表达，其中一些研究表明这些受体可能会干扰痛觉感受。本研究调查了PAR(1)在炎性疼痛中的作用及其相关机制。足底注射PAR(1)激动剂可增加撤针潜伏期，并降低对von Frey细丝的反应频率，从而抑制小鼠对机械和热刺激的伤害性反应。PAR(1)激动剂还可减轻角叉菜胶诱导的炎性痛觉过敏。PAR(1)激动剂的抗伤害性作用是由内源性阿片类物质介导的，因为局部注射甲基碘化纳洛酮可抑制这种作用，且足底注射PAR(1)激动剂可增加内源性阿片类物质前体脑啡肽原的mRNA表达。然而，PAR(1)激动剂无法抑制暴露于伤害性刺激剂的离体感觉神经元中的钙信号。最后，尽管炎症参数相似，但与野生型小鼠相比，PAR(1)基因缺陷小鼠在足底注射福尔马林或角叉菜胶诱导的炎性痛觉过敏中，或在胶原诱导性关节炎的慢性模型中，均表现出强烈的痛觉过敏增强。这项研究突出了一种此前未知的内源性镇痛机制，表明凝血酶受体PAR(1)在炎性疼痛调节中以及作为阿片类途径激活剂发挥着核心作用。
