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Suberoylanilide Hydroxamic Acid Ameliorates Pain Sensitization in Central Neuropathic Pain After Spinal Cord Injury via the HDAC5/NEDD4/SCN9A Axis

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Abstract

Pain sensitization in spinal cord injury (SCI)-induced central neuropathic pain has been a research target. Additionally, suberoylanilide hydroxamic acid (SAHA) has been reported to protect against pain hypersensitivity in central neuropathic pain. Hence, this research probed the impact of SAHA on pain sensitization in central neuropathic pain after SCI via the HDAC5/NEDD4/SCN9A axis. After SAHA treatment, SCI modeling, and gain- and loss-of-function assays, behavioral analysis was performed in mice to evaluate pain hypersensitivity and anxiety/depression-like behaviors. The enrichment of H3K27Ac in the NEDD4 promoter and the ubiquitination of SCN9A were measured with ChIP and Co-IP assays, respectively. The treatment of SAHA regained paw withdrawal threshold and paw withdrawal latency values, entry time and numbers in the center area, and entry proportion in the open arm for SCI mice, accompanied by decreases in immobility time, eating latency, thermal hyperalgesia, and mechanical ectopic pain. However, SAHA treatment did not affect the motor function of mice. SAHA treatment lowered HDAC5 expression and SCN9A protein expression in SCI mice, as well as enhanced SCN9A ubiquitination and NEDD4 expression. HDAC5 knockdown greatly increased H3K27Ac enrichment in the NEDD4 promoter. NEDD4 upregulation or HDAC5 knockdown elevated SCN9A ubiquitination but diminished SCN9A protein expression in dorsal root ganglions of SCI mice. NEDD4 silencing mitigated the improving effects of SAHA treatment on the pain hypersensitivity and anxiety/depression-like behaviors of SCI mice. SAHA suppressed HDAC5 to augment NEDD4 expression and SCN9A degradation, thereby ameliorating the pain hypersensitivity and anxiety/depression-like behaviors of SCI mice.

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The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

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  1. Changsheng Wang and Rongsheng Chen contributed equally to this research.

Authors and Affiliations

  1. Department of Spinal Surgery, First Affiliated Hospital of Fujian Medical University, No. 20 Chazhong Road, Taijiang District, Fuzhou, 350005, Fujian, People’s Republic of China

    Changsheng Wang, Rongsheng Chen, Xitian Zhu & Xiaobo Zhang

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  1. Changsheng Wang
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  2. Rongsheng Chen
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  3. Xitian Zhu
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Contributions

CW and RC conceived the ideas; designed the experiments. RC and XTZ performed the experiments. XTZ and XBZ analyzed the data. All authors provided critical materials. XTZ and XBZ wrote the manuscript. CW supervised the study. All the authors have read and approved the final version for publication.

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Correspondence to Changsheng Wang.

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Wang, C., Chen, R., Zhu, X. et al. Suberoylanilide Hydroxamic Acid Ameliorates Pain Sensitization in Central Neuropathic Pain After Spinal Cord Injury via the HDAC5/NEDD4/SCN9A Axis. Neurochem Res 48, 2436–2450 (2023). https://doi.org/10.1007/s11064-023-03913-z

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