Upregulation of Chemokine CXCL12 in the Dorsal Root Ganglia and Spinal Cord Contributes to the Development and Maintenance of Neuropathic Pain Following Spared Nerve Injury in Rats
Upregulation of Chemokine CXCL12 in the Dorsal Root Ganglia and Spinal Cord Contributes to the Development and Maintenance of Neuropathic Pain Following Spared Nerve Injury in Rats
复制标题
背根神经节和脊髓中趋化因子 CXCL12 的上调有助于大鼠神经损伤后神经病理性疼痛的发生和维持
DOI：
10.1007/s12264-015-0007-4
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发表时间：
2016-02-01
影响因子：
5.6
通讯作者：
Xu, Ji-Tian
中科院分区：
文献类型：
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作者：
Bai, Liying;Wang, Xinru;Xu, Ji-Tian
新的证据表明，CXCL12/CXCR4信号通路参与慢性疼痛。然而，很少有研究系统地评估其在直接神经损伤引起的神经性疼痛中的作用及其潜在机制。本研究发现，SNI可增加腰椎5背根神经节（DRG）神经元和卫星胶质细胞中CXCL12及其同源受体CXCR4的表达。SNI还诱导同侧L4-5脊髓背角中CXCL12和CXCR4的持续上调，其特征是CXCL12在神经元和小胶质细胞中表达，CXCR4在神经元和星形胶质细胞中表达。此外，sni诱导DRG和脊髓中TNF-α表达持续增加。腹腔注射TNF-α合成抑制剂沙利度胺（thalidomide）可降低sni诱导的机械超敏反应，抑制DRG和脊髓中CXCL12的表达。SNI前30分钟和SNI后7天鞘内注射CXCR4拮抗剂AMD3100可减少异常性痛的行为体征。大鼠在SNI治疗第8天ig或ig注射AMD3100后，异常疼痛行为减弱。SNI后产生的神经性疼痛也可通过给予cxcl12中和抗体而受损。此外，重复给药AMD3100可阻止脊髓中ERK的激活。MEK抑制剂PD98059预处理可减轻CXCL12致naïve大鼠的机械超敏反应。综上所述，我们的研究结果表明，TNF-α可能介导SNI后DRG和脊髓中CXCL12的上调，并且CXCL12/CXCR4信号通路通过aerk激活参与神经性疼痛的发生和维持。
Emerging evidence indicates that CXCL12/CXCR4 signaling is involved in chronic pain. However, few studies have systemically assessed its role in direct nerve injury-induced neuropathic pain and the underlying mechanism. Here, we determined that spared nerve injury (SNI) increased the expression of CXCL12 and its cognate receptor CXCR4 in lumbar 5 dorsal root ganglia (DRG) neurons and satellite glial cells. SNI also induced long-lasting upregulation of CXCL12 and CXCR4 in the ipsilateral L4–5 spinal cord dorsal horn, characterized by CXCL12 expression in neurons and microglia, and CXCR4 expression in neurons and astrocytes. Moreover, SNI-induced a sustained increase in TNF-α expression in the DRG and spinal cord. Intraperitoneal injection (i.p.) of the TNF-α synthesis inhibitor thalidomide reduced the SNI-induced mechanical hypersensitivity and inhibited the expression of CXCL12 in the DRG and spinal cord. Intrathecal injection (i.t.) of the CXCR4 antagonist AMD3100, both 30 min before and 7 days after SNI, reduced the behavioral signs of allodynia. Rats given an i.t. or i.p. bolus of AMD3100 on day 8 of SNI exhibited attenuated abnormal pain behaviors. The neuropathic pain established following SNI was also impaired by i.t. administration of a CXCL12-neutralizing antibody. Moreover, repetitive i.t. AMD3100 administration prevented the activation of ERK in the spinal cord. The mechanical hypersensitivity induced in naïve rats by i.t. CXCL12 was alleviated by pretreatment with the MEK inhibitor PD98059. Collectively, our results revealed that TNF-α might mediate the upregulation of CXCL12 in the DRG and spinal cord following SNI, and that CXCL12/CXCR4 signalingviaERK activation contributes to the development and maintenance of neuropathic pain.