After brachial plexus avulsion (BPA), microglia induce inflammation, initiating and maintaining neuropathic pain. EZH2 (enhancer of zeste homolog 2) has been implicated in inflammation and neuropathic pain, but the mechanisms by which it regulates neuropathic pain remain unclear. Here, we found that EZH2 levels were markedly upregulated during BPA-induced neuropathic pain in vivo and in vitro, stimulating pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) secretion in vivo. In rats with BPA-induced neuropathic pain, mechanical and cold hypersensitivities were induced by EZH2 upregulation and inhibited by EZH2 downregulation in the anterior cingulate cortex. Microglial autophagy was also significantly inhibited, with EZH2 inhibition activating autophagy and reducing neuroinflammation in vivo. However, this effect was impaired by inhibiting autophagy with 3-methyladenine, suggesting that the MTOR signaling pathway is a functional target of EZH2. These data suggest that EZH2 regulates neuroinflammation and neuropathic pain via a novel MTOR-mediated autophagy signaling pathway, providing a promising approach for managing neuropathic pain.

中文翻译：

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通过抑制大鼠臂丛撕脱后的自噬，前扣带回皮层小胶质细胞中的EZH2水平升高可加重神经性疼痛。

臂丛神经撕脱（BPA）后，小胶质细胞引起炎症，引发并维持神经性疼痛。EZH2（zeste同源物2的增强剂）与炎症和神经性疼痛有关，但其调节神经性疼痛的机制尚不清楚。在这里，我们发现在BPA引起的体内和体外神经性疼痛期间，EZH2水平显着上调，刺激了体内促炎细胞因子（IL-1β，TNF-α和IL-6）的分泌。。在BPA引起的神经性疼痛的大鼠中，前扣带回皮质中EZH2上调诱导了机械性和冷性超敏反应，而EZH2下调则抑制了机械性和冷性超敏反应。小胶质细胞自噬也被显着抑制，EZH2抑制可在体内激活自噬并减少神经炎症。但是，此作用被3-甲基腺嘌呤抑制自噬而受到削弱，表明MTOR信号通路是EZH2的功能靶标。这些数据表明，EZH2通过新颖的MTOR介导的自噬信号通路调节神经炎症和神经性疼痛，为治疗神经性疼痛提供了有希望的方法。