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首页> 外文期刊>CNS neuroscience & therapeutics. >CXCL12/CXCR4 signaling contributes to neuropathic pain via central sensitization mechanisms in a rat spinal nerve ligation model
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CXCL12/CXCR4 signaling contributes to neuropathic pain via central sensitization mechanisms in a rat spinal nerve ligation model

机译：CXCL12 / CXCR4信号传导通过大鼠脊髓神经结扎模型中的中枢敏化机制促进神经性疼痛

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Background Previous studies have demonstrated that the CXCL12/CXCR4 signaling axis is involved in the regulation of neuropathic pain (NP). Here, we performed experiments to test whether the CXCL12/CXCR4 signaling pathway contributes to the pathogenesis of neuropathic pain after spinal nerve ligation (SNL) via central sensitization mechanisms. Methods Neuropathic pain was induced and assessed in a SNL rat model. The expression and distribution of CXCL12 or CXCR4 were examined by immunofluorescence staining and western blot. The effects of CXCL12 rat peptide, CXCL12 neutralizing antibody, CXCR4 antagonist, and astrocyte metabolic inhibitor on pain hypersensitivity were explored by behavioral tests in naive or SNL rats. We measured the expression level of c‐Fos and CGRP to evaluate the sensitization of neurons by RT‐PCR. The activation of astrocyte and microglia was analyzed by measuring the level of GFAP and iba‐1. The mRNA levels of the pro‐inflammatory cytokines such as TNF‐α, IL‐1β, and IL‐6 and Connexin 30, Connexin 43, EAAT 1, EAAT 2 were also detected by RT‐PCR. Results First, we found that the expression of CXCL12 and CXCR4 was upregulated after SNL. CXCL12 was mainly expressed in the neurons while CXCR4 was expressed both in astrocytes and neurons in the spinal dorsal horn after SNL. Moreover, intrathecal administration of rat peptide, CXCL12, induced hypersensitivity in naive rats, which was partly reversed by fluorocitrate. In addition, the CXCL12 rat peptide increased mRNA levels of c‐Fos, GFAP, and iba‐1. A single intrathecal injection of CXCL12 neutralizing antibody transiently reversed neuropathic pain in the SNL rat model. Consecutive use of CXCL12 neutralizing antibody led to significant delay in the induction of neuropathic pain, and reduced the expression of GFAP and iba‐1 in the spinal dorsal horn. Finally, repeated intrathecal administration of the CXCR4 antagonist, AMD3100, significantly suppressed the initiation and duration of neuropathic pain. The mRNA levels of c‐Fos, CGRP, GFAP, iba‐1, and pro‐inflammatory cytokines, also including Connexin 30 and Connexin 43 were decreased after injection of AMD3100, while EAAT 1 and EAAT 2 mRNAs were increased. Conclusion We demonstrate that the CXCL12/CXCR4 signaling pathway contributes to the development and maintenance of neuropathic pain via central sensitization mechanisms. Importantly, intervening with CXCL12/CXCR4 presents an effective therapeutic approach to treat the neuropathic pain.
机译：背景技术先前的研究表明，CXCL12 / CXCR4信号轴参与神经性疼痛（NP）的调节。在这里，我们进行了实验，以测试CXCL12 / CXCR4信号通路是否通过中枢敏化机制促进了脊髓神经结扎（SNL）后神经性疼痛的发病机理。方法在SNL大鼠模型中诱发并评估神经性疼痛。通过免疫荧光染色和western blot检查CXCL12或CXCR4的表达和分布。通过行为试验在幼稚或SNL大鼠中探索了CXCL12大鼠肽，CXCL12中和抗体，CXCR4拮抗剂和星形胶质细胞代谢抑制剂对疼痛超敏反应的影响。我们测量了c-Fos和CGRP的表达水平，以通过RT-PCR评估神经元的敏感性。通过测量GFAP和iba-1的水平来分析星形胶质细胞和小胶质细胞的活化。还通过RT-PCR检测了促炎细胞因子（如TNF-α，IL-1β和IL-6和连接蛋白30，连接蛋白43，EAAT 1，EAAT 2）的mRNA水平。结果首先，我们发现SNL后CXCL12和CXCR4的表达上调。 SNL后，CXCL12主要在神经元中表达，而CXCR4在星形胶质细胞和脊髓背角神经元中均表达。此外，鞘内注射大鼠肽CXCL12会在幼稚大鼠中引起超敏反应，而氟柠檬酸可部分逆转超敏反应。此外，CXCL12大鼠肽增加了c-Fos，GFAP和iba-1的mRNA水平。鞘内注射CXCL12中和抗体可在SNL大鼠模型中短暂逆转神经性疼痛。连续使用CXCL12中和抗体会导致神经性疼痛的诱导显着延迟，并降低脊髓背角中GFAP和iba-1的表达。最后，CXCR4拮抗剂AMD3100的鞘内重复给药显着抑制了神经性疼痛的发生和持续时间。注射AMD3100后，c-Fos，CGRP，GFAP，iba-1和促炎细胞因子（包括连接蛋白30和连接蛋白43）的mRNA水平降低，而EAAT 1和EAAT 2 mRNA则升高。结论我们证明了CXCL12 / CXCR4信号通路通过中枢敏化机制促进了神经性疼痛的发生和维持。重要的是，干预CXCL12 / CXCR4提供了一种有效的治疗方法，可治疗神经性疼痛。

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