Involvement of microglial P2X7 receptors and downstream signaling pathways in long-term potentiation of spinal nociceptive responses
Involvement of microglial P2X7 receptors and downstream signaling pathways in long-term potentiation of spinal nociceptive responses
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小胶质细胞 P2X7 受体和下游信号通路参与脊髓伤害性反应的长期增强
DOI：
10.1016/j.bbi.2010.06.001
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发表时间：
2010-10-01
影响因子：
15.1
通讯作者：
Zhao, Zhi-Qi
中科院分区：
文献类型：
--
作者：
Chu, Yu-Xia;Zhang, Yan;Zhao, Zhi-Qi
强直刺激坐骨神经(TSS)产生脊髓中C纤维诱发的场电位的长时程增强(LTP)。这种增强被认为是脊椎疼痛通路中持久敏化的底物。由于小胶质细胞已被证明调节脊髓LTP的诱导，我们推测，主要表达于小胶质细胞并参与小胶质细胞与神经元之间通讯的P2X7受体(P2X7R)可能在这一诱导过程中发挥作用。本研究探讨了P2X7R5在TSS诱导的大鼠脊髓长时程增强和持续性疼痛中的作用。在活体和体外脊髓切片中，P2X7R拮抗剂OxATP或BBG均可阻止脊髓LTP的诱导，并减轻机械性痛觉过敏。用P2X7-siRNA下调P2X7R5可阻断脊髓LTP的诱导，并抑制机械性痛觉异常。双重免疫荧光显示，P2X7R5与小胶质细胞标记OX-42共存，而与星形胶质细胞标记GFAP或神经元标记Neun不共存。鞘内注射BBG可抑制脊髓背角浅层小胶质细胞P2X7R5表达上调和Fos表达增加。此外，预先给予BBG可抑制TSS后小胶质细胞标志物Iba-1、磷酸化p38(p-p38)、白介素1β(IL-1β)和GluR1的表达增加。预先给予IL-1受体拮抗剂(IL-1ra)可阻断脊髓LIP的诱导和GluR1的上调。这些结果提示，小胶质细胞P2X7Rs及其下游信号通路在TSS诱导脊髓LTP和持续性疼痛中起着关键作用。(C)2010 Elsevier Inc.保留所有权利。
Tetanic stimulation of the sciatic nerve (TSS) produces long-term potentiation (LTP) of C-fiber-evoked field potentials in the spinal cord. This potentiation is considered to be a substrate for long-lasting sensitization in the spinal pain pathway. Because microglia have previously been shown to regulate the induction of spinal LTP, we hypothesize that P2X7 receptors (P2X7R), which are predominantly expressed in microglia and participate in the communication between microglia and neurons, may play a role in this induction. This study investigated the potential roles of P2X7R5 in spinal LTP and persistent pain induced by TSS in rats. OxATP or BBG, a P2X7R antagonist, prevented the induction of spinal LTP both in vivo and in spinal cord slices in vitro and alleviated mechanical allodynia. Down-regulation of P2X7R5 with P2X7-siRNA blocked the induction of spinal LTP and inhibited mechanical allodynia. Double immunofluorescence showed colocalization of P2X7R5 with the microglial marker OX-42, but not with the astrocytic marker GFAP or the neuronal marker NeuN. Intrathecal injection of BBG suppressed the up-regulation of microglial P2X7R5 and increased expression of Fos in the spinal superficial dorsal horn. Further, pre-administration of BBG inhibited increased expression of the microglial marker Iba-1, phosphorylated p38 (p-p38), interleukin 1 beta (IL-1 beta) and GluR1 following TSS. Pre-administration of the IL-1 receptor antagonist (IL-1ra) blocked both the induction of spinal LIP and the up-regulation of GluR1. These results suggest that microglial P2X7Rs and its downstream signaling pathways play a pivotal role in the induction of spinal LTP and persistent pain induced by TSS. (C) 2010 Elsevier Inc. All rights reserved.