Li Baolong, Yu Kaiming, Zhou Xiongyao, Sun Jialu, Qi Le, Li Weiye, Yang Tuo, Li Weizhen, Wang Ningning, Gu Xiaosong, Cui Shusen, Cao Rangjuan
Department of Hand and Foot Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.
Key Laboratory of Peripheral Nerve Injury and Regeneration of Jilin Province, Changchun, China.
J Headache Pain. 2025 Jan 27;26(1):16. doi: 10.1186/s10194-025-01953-0.
Neuropathic pain poses a significant clinical challenge, largely due to the incomplete understanding of its molecular mechanisms, particularly the role of mitochondrial dysfunction. Bioinformatics analysis revealed that pyroptosis and inflammatory responses induced by spared nerve injury (SNI) in the spinal dorsal horn play a critical role in the initiation and persistence of neuropathic pain. Among the factors involved, TSPO (translocator protein) emerged as a key regulator. Our experimental findings showed that TSPO expression was upregulated during neuropathic pain, accompanied by mitochondrial dysfunction, specifically manifested as impaired mitochondrial biogenesis, disrupted mitochondrial dynamics (including insufficient expression of mitochondrial biogenesis and fusion-related proteins, as well as significantly increased expression of fission-related proteins), and activation of pyroptosis. Pharmacological upregulation of TSPO, but not its downregulation, effectively alleviated SNI-induced pain hypersensitivity, improving mitochondrial function and reducing pyroptosis. Immunofluorescence staining confirmed that TSPO was primarily localized in astrocytes, and its expression mirrored the protective effects on mitochondrial health and pyroptosis prevention. PCR array analysis suggested a strong association between TSPO and the mitochondrial regulation pathway AMPK-PGC-1α. Notably, inhibition of AMPK-PGC-1α abolished TSPO effects on mitochondrial balance and pyroptosis suppression. Furthermore, Mendelian randomization analysis of GWAS data indicated that increased TSPO expression was linked to pain relief. Through drug screening, molecular docking, and behavioral assays, we identified zopiclone as a promising TSPO-targeting drug for pain treatment. In summary, this study enhances our understanding of the molecular interplay between TSPO, mitochondrial health, and neuropathic pain, highlighting TSPO as a potential therapeutic target for pain management.
神经性疼痛带来了重大的临床挑战，这主要是由于对其分子机制，尤其是线粒体功能障碍的作用了解不全面。生物信息学分析表明，脊髓背角 spared 神经损伤（SNI）诱导的细胞焦亡和炎症反应在神经性疼痛的起始和持续中起关键作用。在涉及的因素中，TSPO（转位蛋白）成为关键调节因子。我们的实验结果表明，在神经性疼痛期间 TSPO 表达上调，同时伴有线粒体功能障碍，具体表现为线粒体生物合成受损、线粒体动力学紊乱（包括线粒体生物合成和融合相关蛋白表达不足，以及裂变相关蛋白表达显著增加）和细胞焦亡激活。TSPO 的药理学上调而非下调有效减轻了 SNI 诱导的疼痛超敏反应，改善了线粒体功能并减少了细胞焦亡。免疫荧光染色证实 TSPO 主要定位于星形胶质细胞，其表达反映了对线粒体健康的保护作用和对细胞焦亡的预防作用。PCR 阵列分析表明 TSPO 与线粒体调节途径 AMPK-PGC-1α 之间存在密切关联。值得注意的是，抑制 AMPK-PGC-1α 消除了 TSPO 对线粒体平衡和细胞焦亡抑制的作用。此外，对全基因组关联研究（GWAS）数据的孟德尔随机化分析表明，TSPO 表达增加与疼痛缓解有关。通过药物筛选、分子对接和行为分析，我们确定佐匹克隆是一种有前景的靶向 TSPO 的疼痛治疗药物。总之，本研究增进了我们对 TSPO、线粒体健康和神经性疼痛之间分子相互作用的理解，突出了 TSPO 作为疼痛管理潜在治疗靶点的地位。
