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

Background: 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. Results: 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 naive 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 1 beta, and interleukin 6 in the ipsilateral L3-L5 segment of spinal cord in the pSNL and CPIP models on POD 3. Conclusion: 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.