中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (2): 370-377.doi: 10.4103/1673-5374.317989

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

高频脊髓刺激恢复脊髓背角溶酶体功能和自噬通量产生持久的镇痛作用

  

  • 出版日期:2022-02-15 发布日期:2021-10-08

High-frequency spinal cord stimulation produces long-lasting analgesic effects by restoring lysosomal function and autophagic flux in the spinal dorsal horn

Zhi-Bin Wang1, Yong-Da Liu1, Shuo Wang2, Ping Zhao1, *   

  1. 1Department of Anesthesiology and Pain Management, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China; 2Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
  • Online:2022-02-15 Published:2021-10-08
  • Contact: Ping Zhao, MD, zhaoping_sj@163.com or zhaop@sj-hospital.org.
  • Supported by:
    This work was supported by the National Nature Science Foundation of China, No. 81870838; Liaoning Province Distinguished Professor Support Program of China, No. XLYC1802096; Shenyang Clinical Medicine Research Center of Anesthesiology of China, Nos. 19-110-4-24, 20-204-4-44; and the Outstanding Scientific Foundation of Shengjing Hospital of China, No. 201708 (all to PZ).

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摘要：

高频脊髓刺激被认为是治疗神经性疼痛的有效方法，但其具体镇痛机制尚有待研究。实验以脊神经结扎诱发成年大鼠神经性疼痛，2d后在脊髓背角行4h的高频脊髓刺激强度为自身运动阈值的50%，频率10,000 Hz，脉冲宽度0.024 ms。结果可见：（1）由于应用高频脊髓刺激，损伤大鼠的触觉异常性疼痛得到了明显缓解，且在刺激停止后效果仍能持续3h；（2）高频脊髓刺激恢复了溶酶体功能，并增加脊髓前角中LAMP2和matu-CTSD的表达，缓解自噬标志物LC3-II或P62表达的异常升高；（3）高频脊髓刺激恢复了脊髓背角浅层中与神经元共定位的LAMP2免疫反应性；（4）脊髓刺激前60min腹腔注射15 mg/kg氯喹，可逆转上述蛋白的表达，且可缩短高频脊髓刺激的镇痛时间；（5）实验结果提示高频脊髓刺激可通过恢复脊髓背角的溶酶体功能及自噬通量，实现了对神经性疼痛大鼠的长期镇痛作用。实验于2017年3月1日经中国医科大学动物伦理委员会批准（批准号2017PS196K）。

https://orcid.org/0000-0001-6392-5391 (Ping Zhao)

关键词: font-family:宋体, ">高频脊髓刺激, 电刺激, 神经性疼痛, 镇痛, 自噬溶酶体, 功能障碍, 脊神经结扎, 脊髓背角

Abstract: High-frequency spinal cord stimulation (HF-SCS) has been established as an effective therapy for neuropathic pain. However, the analgesic mechanisms involved in HF-SCS remain to be clarified. In our study, adult rat neuropathic pain was induced by spinal nerve ligation. Two days after modeling, the rats were subjected to 4 hours of HF-SCS (motor threshold 50%, frequency 10,000 Hz, and pulse width 0.024 ms) in the dorsal horn of the spinal cord. The results revealed that the tactile allodynia of spinal nerve-injured rats was markedly alleviated by HF-SCS, and the effects were sustained for 3 hours after the stimulation had ceased. HF-SCS restored lysosomal function, increased the levels of lysosome-associated membrane protein 2 (LAMP2) and the mature form of cathepsin D (matu-CTSD), and alleviated the abnormally elevated levels of microtubule-associated protein 1A/B-light chain 3 (LC3)-II and sequestosome 1 (P62) in spinal nerve-injured rats. HF-SCS also mostly restored the immunoreactivity of LAMP2, which was localized in neurons in the superficial layers of the spinal dorsal horn in spinal nerve-injured rats. In addition, intraperitoneal administration of 15 mg/kg chloroquine for 60 minutes reversed the expression of the aforementioned proteins and shortened the timing of the analgesic effects of HF-SCS. These findings suggest that HF-SCS may exhibit long-lasting analgesic effects on neuropathic pain in rats through improving lysosomal dysfunction and alleviating autophagic flux. This study was approved by the Laboratory Animal Ethics Committee of China Medical University, Shenyang, China (approval No. 2017PS196K) on March 1, 2017.

Key words: autolysosome, dorsal horn of spinal cord, dysfunction, electrical stimulation, high-frequency spinal cord stimulation, neuropathic pain, spinal nerve ligation

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