Department of Psychiatry and Psychotherapy, Section of Molecular Psychiatry, University of Freiburg, Freiburg, Germany.
EMBO J. 2011 May 4;30(9):1864-73. doi: 10.1038/emboj.2011.89. Epub 2011 Mar 25.
Up-regulation of P2X4 receptors in spinal cord microglia is crucial for tactile allodynia, an untreatable pathological pain reaction occurring after peripheral nerve injury. How nerve injury in the periphery leads to this microglia reaction in the dorsal horn of the spinal cord is not yet understood. It is shown here that CCL21 was rapidly expressed in injured small-sized primary sensory neurons and transported to their central terminals in the dorsal horn. Intrathecal administration of a CCL21-blocking antibody diminished tactile allodynia development in wild-type animals. Mice deficient for CCL21 did not develop any signs of tactile allodynia and failed to up-regulate microglial P2X4 receptor expression. Microglia P2X4 expression was enhanced by CCL21 application in vitro and in vivo. A single intrathecal injection of CCL21 to nerve-injured CCL21-deficient mice induced long-lasting allodynia that was undistinguishable from the wild-type response. This effect of CCL21 injection was strictly dependent on P2X4 receptor function. Since neuronal CCL21 is the earliest yet identified factor in the cascade leading to tactile allodynia, these findings may lead to a preventive therapy in neuropathic pain.
脊髓小胶质细胞中 P2X4 受体的上调对于触觉过敏至关重要，触觉过敏是外周神经损伤后发生的一种无法治疗的病理性疼痛反应。目前尚不清楚外周神经损伤如何导致脊髓背角中小胶质细胞的这种反应。本文显示，CCL21 在受伤的小尺寸初级感觉神经元中迅速表达，并被运送到其在背角的中枢末端。鞘内给予 CCL21 阻断抗体可减少野生型动物触觉过敏的发展。缺乏 CCL21 的小鼠没有出现任何触觉过敏迹象，也没有上调小胶质细胞 P2X4 受体表达。CCL21 在体外和体内均可增强小胶质细胞 P2X4 表达。鞘内单次注射 CCL21 到神经损伤的 CCL21 缺陷小鼠中，可诱导持久的触觉过敏，与野生型反应无明显区别。CCL21 注射的这种作用严格依赖于 P2X4 受体功能。由于神经元 CCL21 是导致触觉过敏级联反应中最早确定的因素，这些发现可能为治疗神经性疼痛提供预防疗法。
