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Dexmedetomidine Alleviates CCI-Induced Neuropathic Pain via Inhibiting HMGB1-Mediated Astrocyte Activation and the TLR4/NF-κB Signaling Pathway in Rats

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Abstract

To investigate the effects of dexmedetomidine on chronic constriction injury (CCI)–induced neuropathic pain and to further explore its mechanism. A CCI rat model was established and treatment with dexmedetomidine. The paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were monitored at different time points, and the effects of hematoxylin-eosin staining on the sciatic nerve morphology of rats were observed. Immunohistochemical and immunofluorescence analyses were used to detect the expression of high mobility group box-1 (HMGB1) protein and glial fibrillary acidic protein (GFAP), and protein fluorescence intensity of GFAP in spinal cord tissue, respectively. Moreover, the expression of HMGB1 and Toll-like receptor-4/nuclear factor kappa-B (TLR4/NF-κB) pathway–related proteins were detected by western blot assay. To verify whether dexmedetomidine alleviates CCI-induced neuropathic pain by inhibiting HMGB1-mediated astrocyte activation and the TLR4/NF-κB signaling pathway, the rats were further treated with an HMGB1 activator or antagonist. Dexmedetomidine was found to improve the pathological changes of the sciatic nerve and alleviate pain in the CCI rats. The expression of HMGB1, GFAP, TLR4, TRAF6, MyD88, and p-P65 were greatly downregulated in the spinal cord tissues of the CCI rats. In addition, a further study showed that an HMGB1 activator can reverse the inhibition of neuropathic pain behaviors of dexmedetomidine. Overexpression of HMGB1 downregulated the PWMT and PWTL and enhanced the astrocyte activity and the TLR4/NF-κB signaling pathway in CCI rats. These results indicated that dexmedetomidine can alleviate neuropathic pain in CCI rats by inhibiting HMGB1-mediated astrocyte activation and the TLR4/NF-κB signaling pathway.

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Author notes

  1. Erxian Zhao and Liying Bai contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450052, Henan Province, China

    Erxian Zhao, Liying Bai, Li Li, Zhongci Dou, Yunli Huang, Yan Li & Yunqi Lv

  2. Center for Anesthesiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100000, China

    Shurong Li

Authors
  1. Erxian Zhao
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  2. Liying Bai
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  3. Shurong Li
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  4. Li Li
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  5. Zhongci Dou
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  6. Yunli Huang
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  7. Yan Li
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  8. Yunqi Lv
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Corresponding author

Correspondence to Yunqi Lv.

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This study was carried out in strict accordance with the recommendations set out in the Guide for the Care and Use of Laboratory Animals (National Institutes of Health Pub. No. 85-23, revised 1996). The protocol was approved by the Animal Ethics Committee

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Significance

Dexmedetomidine may be used to treat neuropathic pain.

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Zhao, E., Bai, L., Li, S. et al. Dexmedetomidine Alleviates CCI-Induced Neuropathic Pain via Inhibiting HMGB1-Mediated Astrocyte Activation and the TLR4/NF-κB Signaling Pathway in Rats. Neurotox Res 38, 723–732 (2020). https://doi.org/10.1007/s12640-020-00245-6

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  • DOI: https://doi.org/10.1007/s12640-020-00245-6

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