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Spinal MCP-1 Contributes to Central Post-stroke Pain by Inducing Central Sensitization in Rats

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Abstract

Central post-stroke pain (CPSP) is a highly refractory form of central neuropathic pain that has been poorly studied mechanistically. Recent observations have emphasized the critical role of the spinal dorsal horn in CPSP. However, the underlying mechanisms remain unclear. In this study, rats were subjected to thalamic hemorrhage to investigate the role of spinal monocyte chemoattractant protein-1 (MCP-1) and C-C motif chemokine receptor 2 (CCR2) in the development of CPSP. Immunohistochemical staining and ELISA were used to assess the expression changes of c-Fos, Iba-1, GFAP, MCP-1, and CCR2 in the dorsal horn of the lumbar spinal cord following thalamic hemorrhage, and the involvement of spinal MCP-1 in CPSP was examined by performing intrathecal anti-MCP-1 mAb injection to neutralize the spinal extracellular MCP-1. We demonstrated that intra-thalamic collagenase microinjection induced persistent bilateral mechanical pain hypersensitivity and facilitated the spontaneous pain behaviors evoked by intraplantar bee venom injection. Accompanying CPSP, the expression of c-Fos, Iba-1, and GFAP in the lumbar spinal dorsal horn was significantly increased up to 28 days post-intra-thalamic collagenase microinjection. Intrathecal injection of minocycline and fluorocitrate dramatically reverses the bilateral mechanical pain hypersensitivity. Moreover, intra-thalamic collagenase microinjection dramatically induced the up-regulation of MCP-1 but had no effect on the expression of CCR2 in the bilateral lumbar spinal dorsal horn, and MCP-1 was primarily localized in the neuron. Intrathecal injection of anti-MCP-1 mAb was also able to reverse CPSP and reduce the expression of c-Fos, Iba-1, and GFAP in the lumbar spinal dorsal horn. These findings indicated that spinal MCP-1 contributes to CPSP by mediating the activation of spinal neurons and glial cells following thalamic hemorrhage stroke, which may provide insights into pharmacologic treatment for CPSP.

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Data Availability

All relevant data supporting the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81801101), the Joint Funds for the Innovation of Science and Technology of Fujian Province (No. 2020Y9043), the Natural Science Foundation of Fujian Province of China (No. 2021J011264, No. 2020J011130 and No. 2022J01490), and the Army’s Youth Cultivation Program (No. 20QNPY073). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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  1. Fei Yang, Jun-Jie Jing, Si-Yin Fu and Xiu-Zhu Su contributed equally to this work.

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  1. Department of Anesthesiology and Perioperative Medicine, Fuzong Clinical College/900th Hospital of the Joint Logistic Support Force, Fujian Medical University, Fuzhou, 350025, China

    Fei Yang, Si-Yin Fu, Xiu-Zhu Su, Yu-Ling Zhong, Dong-Sheng Chen, Xiao-Zhi Wu & Yi-Qing Zou

  2. Department of Anesthesiology and Perioperative Medicine, Dongfang Hospital, Xiamen University, Fuzhou, 350025, China

    Fei Yang, Si-Yin Fu, Xiu-Zhu Su, Yu-Ling Zhong, Dong-Sheng Chen, Xiao-Zhi Wu & Yi-Qing Zou

  3. Pain Research Institute, Fujian Medical University, Fuzhou, 350025, China

    Fei Yang

  4. Department of Neurosurgery, Fujian Children’s Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350025, China

    Jun-Jie Jing

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All authors have contributed significantly to this work. FY, YQZ, XZW, and JJJ conceived and designed the experiments; FY and SYF performed most of the experiments; XZS, YLZ, and DSC contributed to data collection and provided experimental support; DSC, YQZ, and FY analyzed and interpreted the data; FY wrote the manuscript; YQZ and XZW revised and edited the manuscript. All authors read and approved the final manuscript.

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Correspondence to Dong-Sheng Chen, Xiao-Zhi Wu or Yi-Qing Zou.

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Yang, F., Jing, JJ., Fu, SY. et al. Spinal MCP-1 Contributes to Central Post-stroke Pain by Inducing Central Sensitization in Rats. Mol Neurobiol 60, 2086–2098 (2023). https://doi.org/10.1007/s12035-022-03184-9

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