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Crosstalk between astrocytic CXCL12 and microglial CXCR4 contributes to the development of neuropathic pain

机译：星形细胞CXCL12和小胶质细胞CXCR4之间的串扰有助于神经性疼痛的发展

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Chemokine axis chemokine C-X-C motif ligand 12/C-X-C chemokine receptor type 4 (CXCL12/CXCR4) is an emerging pain modulator, but mechanisms for its involvement in neuropathic pain remain unclear. Here, we aimed to study whether CXCL12/CXCR4 axis modulated the development of neuropathic pain via glial mechanisms. In this study, two mouse models of neuropathic pain, namely partial sciatic nerve ligation (pSNL) model and chronic post-ischemia pain (CPIP) model, were used. In the dorsal horn of L3–L5 segment of spinal cord, CXCL12 and CXCR4 were expressed in both astrocyte and microglia in normal mice. In the pSNL or CPIP model, the expression level of CXCL12 in the ipsilateral L3–L5 segment of mice spinal cord was increased in an astrocyte-dependent manner on post-operative day (POD) 3. Intrathecal administration of CXCL12 with AMD3100 (CXCR4 antagonist) or minocycline (microglia activation inhibitor), but not fluorocitrate (astrocyte activation inhibitor), reversed CXCL12-indued mechanical allodynia in na?ve mice. In these models, AMD3100 and AMD3465 (CXCR4 antagonist), administered daily from 1?h before surgery and up to POD 3, attenuated the development of mechanical allodynia. Moreover, AMD3100 administered daily from 1?h before surgery and up to POD 3 downregulated mRNA levels of tumor necrosis factor alpha, interleukin 1β, and interleukin 6 in the ipsilateral L3–L5 segment of spinal cord in the pSNL and CPIP models on POD 3. This study demonstrates the crosstalk between astrocytic CXCL12 and microglial CXCR4 in the pathogenesis of neuropathic pain using pSNL and CPIP models. Our results offer insights for the future research on CXCL12/CXCR4 axis and neuropathic pain therapy.
机译：趋化因子轴趋化因子C-X-C基序配体12 / C-X-C趋化因子受体4型（CXCL12 / CXCR4）是一种新兴的疼痛调节剂，但其参与神经性疼痛的机制仍不清楚。在这里，我们旨在研究CXCL12 / CXCR4轴是否通过神经胶质机制调节神经性疼痛的发展。在这项研究中，使用了两种小鼠神经性疼痛模型，即局部坐骨神经结扎（pSNL）模型和慢性缺血后疼痛（CPIP）模型。在脊髓L3-L5段的背角，正常小鼠的星形胶质细胞和小胶质细胞中均表达CXCL12和CXCR4。在pSNL或CPIP模型中，术后第3天，星形胶质细胞依赖性方式提高了小鼠脊髓同侧L3-L5节中CXCL12的表达水平。鞘内注射CXCL12与AMD3100（CXCR4拮抗剂） ）或米诺环素（小胶质细胞活化抑制剂），但不改变氟柠檬酸（星形胶质细胞活化抑制剂），可逆转CXCL12诱导的幼稚小鼠机械性异常性疼痛。在这些模型中，AMD3100和AMD3465（CXCR4拮抗剂）在手术前1小时至POD 3每天给药，可减轻机械性异常性疼痛的发生。此外，AMD3100从手术前1小时开始每天给药，直至POD 3降低了POD 3上pSNL和CPIP模型脊髓同侧L3–L5区段中肿瘤坏死因子α，白介素1β和白介素6的mRNA水平。这项研究使用pSNL和CPIP模型证明了星形胶质细胞CXCL12和小胶质细胞CXCR4在神经性疼痛发病机理中的相互影响。我们的结果为CXCL12 / CXCR4轴和神经性疼痛疗法的未来研究提供了见识。

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