Downregulation of Mfn2 Contributes to Chronic Postsurgical Pain via Inducing the Pyroptosis of GABAergic Neurons in the Spinal Cord

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-07-09 DOI:10.1111/cns.70508

Yingjie Hu, Xiao He, Hu Zang, Yuye Chen, Li Li, Tongtong Liu, Li Wan, Chang Zhu, Wenlong Yao

{"title":"Downregulation of Mfn2 Contributes to Chronic Postsurgical Pain via Inducing the Pyroptosis of GABAergic Neurons in the Spinal Cord","authors":"Yingjie Hu, Xiao He, Hu Zang, Yuye Chen, Li Li, Tongtong Liu, Li Wan, Chang Zhu, Wenlong Yao","doi":"10.1111/cns.70508","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Chronic postoperative pain (CPSP) is a significant public health issue due to the complex pathophysiological mechanism. Existing evidence has pointed out that the loss of gamma-aminobutyric acid-ergic (GABAergic) neurons played a critical role in various neuropathic pain models. Previous studies also found that pyroptosis-mediated neuroinflammation was involved in neuropathological pain. However, it remains unclear what the relationship is between pyroptosis and the loss of spinal GABAergic neurons in CPSP. This study aimed to investigate the role and mechanism of GABAergic neuron pyroptosis in CPSP.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>We used skin/muscle incision and retraction (SMIR) to establish the CPSP model in rats. Mechanical allodynia was assessed using the Von Frey test. Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence, biochemical assay, and transmission electron microscope (TEM) were employed to investigate the role and mechanism of GABAergic neuron pyroptosis during CPSP.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>We observed the pyroptosis of GABAergic neurons in the spinal cord following SMIR. Intrathecal administration of the GSDMD inhibitor decreased the pyroptosis of GABAergic neurons in the spinal cord and reversed SMIR-induced mechanical allodynia. In addition, we found that SMIR induced a significant decrease in the level of Mfn2 in the neurons, accompanied by mitochondrial dysfunction and reactive oxygen species (ROS) accumulation in SMIR rats. Intrathecal injection of the Mfn2 activator reduced mitochondrial dysfunction and ROS, alleviated the pyroptosis of GABAergic neurons in the spinal cord, which alleviated the SMIR-induced mechanical allodynia.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>Our study demonstrated that downregulation of Mfn2 leads to mitochondrial dysfunction and ROS accumulation, which promotes the pyroptosis of spinal GABAergic neurons and the development of chronic pain.</p>\n </section>\n </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 7","pages":""},"PeriodicalIF":5.0000,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70508","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"CNS Neuroscience & Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cns.70508","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Chronic postoperative pain (CPSP) is a significant public health issue due to the complex pathophysiological mechanism. Existing evidence has pointed out that the loss of gamma-aminobutyric acid-ergic (GABAergic) neurons played a critical role in various neuropathic pain models. Previous studies also found that pyroptosis-mediated neuroinflammation was involved in neuropathological pain. However, it remains unclear what the relationship is between pyroptosis and the loss of spinal GABAergic neurons in CPSP. This study aimed to investigate the role and mechanism of GABAergic neuron pyroptosis in CPSP.

Methods

We used skin/muscle incision and retraction (SMIR) to establish the CPSP model in rats. Mechanical allodynia was assessed using the Von Frey test. Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence, biochemical assay, and transmission electron microscope (TEM) were employed to investigate the role and mechanism of GABAergic neuron pyroptosis during CPSP.

Results

We observed the pyroptosis of GABAergic neurons in the spinal cord following SMIR. Intrathecal administration of the GSDMD inhibitor decreased the pyroptosis of GABAergic neurons in the spinal cord and reversed SMIR-induced mechanical allodynia. In addition, we found that SMIR induced a significant decrease in the level of Mfn2 in the neurons, accompanied by mitochondrial dysfunction and reactive oxygen species (ROS) accumulation in SMIR rats. Intrathecal injection of the Mfn2 activator reduced mitochondrial dysfunction and ROS, alleviated the pyroptosis of GABAergic neurons in the spinal cord, which alleviated the SMIR-induced mechanical allodynia.

Conclusions

Our study demonstrated that downregulation of Mfn2 leads to mitochondrial dysfunction and ROS accumulation, which promotes the pyroptosis of spinal GABAergic neurons and the development of chronic pain.

Abstract Image

查看原文本刊更多论文

Mfn2下调通过诱导脊髓gaba能神经元焦亡参与慢性术后疼痛

背景慢性术后疼痛（CPSP）由于其复杂的病理生理机制而成为一个重大的公共卫生问题。现有证据表明，γ -氨基丁酸能（GABAergic）神经元的丧失在各种神经性疼痛模型中起着关键作用。以往的研究也发现焦热介导的神经炎症参与了神经病理性疼痛。然而，在CPSP中，焦亡与脊髓gaba能神经元的丧失之间的关系尚不清楚。本研究旨在探讨gaba能神经元焦亡在CPSP中的作用及机制。方法采用皮肤/肌肉切开后收（SMIR）法建立大鼠CPSP模型。采用Von Frey试验评估机械异常性痛。采用Western blotting、定量实时聚合酶链反应（qRT-PCR）、免疫荧光、生化分析和透射电镜（TEM）等方法研究CPSP过程中gaba能神经元焦亡的作用和机制。结果观察到SMIR后脊髓gaba能神经元的焦亡现象。鞘内给予GSDMD抑制剂可减少脊髓中gaba能神经元的焦亡，逆转smir诱导的机械异常性痛。此外，我们发现SMIR诱导大鼠神经元中Mfn2水平显著降低，并伴有线粒体功能障碍和活性氧（ROS）积累。鞘内注射Mfn2激活剂可降低线粒体功能障碍和ROS，减轻脊髓gaba能神经元的焦亡，从而减轻smir诱导的机械异常性痛。结论Mfn2下调可导致线粒体功能障碍和ROS积累，促进脊髓gaba能神经元的焦亡和慢性疼痛的发生。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.