Increased TSPO alleviates neuropathic pain by preventing pyroptosis via the AMPK-PGC-1α pathway

作者：Bao‐Long Li, Kai Yu, Xiongyao Zhou, Jialu Sun, Le Qi, Weiye Li, Tuo Yang, Weizhen Li, Ningning Wang, Xiaosong Gu, Shusen Cui, Rangjuan Cao · 发表于：The Journal of Headache and Pain · 年份：2025 · DOI：10.1186/s10194-025-01953-0 · 被引用次数：15 · 研究领域：Pain Mechanisms and Treatments、Inflammasome and immune disorders、Restless Legs Syndrome Research

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 sup...