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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

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Abstract

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 signaling via ERK activation contributes to the development and maintenance of neuropathic pain.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (31171070, 81171060, 81501070, and 81571079).

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    Authors and Affiliations

    1. Department of Physiology and Neurobiology, Zhengzhou University School of Medicine, Zhengzhou, 450001, China

      Liying Bai, Xinru Wang, Jun-Liang Qian & Ji-Tian Xu

    2. Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China

      Liying Bai, Zhisong Li, Cunlong Kong, Yonghui Zhao, Wei Zhang & Ji-Tian Xu

    3. Department of Pharmacy, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China

      Xinru Wang & Quancheng Kan

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    Bai, L., Wang, X., Li, Z. et al. 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. Neurosci. Bull. 32, 27–40 (2016). https://doi.org/10.1007/s12264-015-0007-4

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