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MiR-672-5p-Mediated Upregulation of REEP6 in Spinal Dorsal Horn Participates in Bortezomib-Induced Neuropathic Pain in Rats

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Abstract

Evidence shows that miRNAs are deeply involved in nervous system diseases, but whether miRNAs contribute to the bortezomib (BTZ)-induced neuropathic pain remains unclear. We aimed to investigate whether miRNAs contribute to bortezomib (BTZ)-induced neuropathic pain and explore the related downstream cascades. The level of miRNAs in the spinal dorsal horn was explored using miRNA microarray and PCR. MiR-672-5p was significantly downregulated in dorsal horn neurons in the rats with BTZ treatment. Intrathecal injection of miR-672-5p agomir blunted the increase of the amplitude and frequency of sEPSCs in dorsal horn neurons and mechanical allodynia induced by BTZ. In addition, the knockdown of miR-672-5p by intrathecal injection of antagomir increased the amplitude and frequency of sEPSCs in dorsal horn neurons and decreased the mechanical withdrawal threshold in naïve rats. Furthermore, silico analysis and the data from subsequent assays indicated that REEP6, a potential miR-672-5p-regulating molecule, was increased in the spinal dorsal horn of rats with BTZ-induced neuropathic pain. Blocking REEP6 alleviated the mechanical pain behavior induced by BTZ, whereas overexpressing REEP6 induced pain hypersensitivity in naïve rats. Importantly, we further found that miR-672-5p was expressed in the REEP6-positive cells, and overexpression or knockdown of miR-672-5p reversely regulated the REEP6 expression. Bioinformatics analysis and double-luciferase reporter assay showed the existence of interaction sites between REEP6 mRNA and miR-672-5p. Overall, our study demonstrated that miR-672-5p directly regulated the expression of REEP6, which participated in the neuronal hyperexcitability in the spinal dorsal horn and neuropathic pain following BTZ treatment. This signaling pathway may potentially serve as a novel therapeutic avenue for chemotherapeutic-induced mechanical hypersensitivity.

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Acknowledgements

This study was funded by National Natural Science Foundation of China (Grant No. 31970936), Natural Science Foundation of Guangdong (2019A1515010871, 2019A1515011447, 2022A1515012259), Guangzhou Science and Technology Plan Project (202206060004).

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Authors and Affiliations

  1. Graduate Department, Department of Sport Medicine, Xi’an Physical Education University, Xi’an, 710068, Shanxi, China

    Yang Sun & Bo Gou

  2. Department of Rehabilitation Medicine, The Second Affiliated Hospital of Xi’an Medical University, Xi’an, Shanxi, China

    Yang Sun

  3. Zhongshan School of Medicine and Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen University, 74 Zhongshan Rd. 2, Guangzhou, 510080, China

    Li Chen, Ting Xu, Wen-Jun Xin & Jia-Yan Wu

  4. Department of Anesthesiology, Huizhou Central People’s Hospital, Huizhou, 516001, Guangdong, China

    Jing-Wen Mai & De-Xing Luo

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  1. Yang Sun
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection were performed by Yang Sun, Li Chen, and Ting Xu. Data analysis were performed by Bo Gou, Jing-Wen Mai and Jia-Yan Wu. The first draft of the manuscript was written by Wen-Jun Xin and Jia-Yan Wu and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jia-Yan Wu.

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Sun, Y., Chen, L., Xu, T. et al. MiR-672-5p-Mediated Upregulation of REEP6 in Spinal Dorsal Horn Participates in Bortezomib-Induced Neuropathic Pain in Rats. Neurochem Res 48, 229–237 (2023). https://doi.org/10.1007/s11064-022-03741-7

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  • DOI: https://doi.org/10.1007/s11064-022-03741-7

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