Neuropathic pain (NeuP) is a chronic and challenging clinical problem, with little effective treatment. Resveratrol has shown neuroprotection by inhibiting inflammatory response in NeuP. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia was identified as a critical factor of inflammation in nervous system diseases. In this study, we explored whether resveratrol could ameliorate neuroinflammation and produce anti-mechanical allodynia effects via regulating TREM2 in spared nerve injury rats, as well as investigated the underlying mechanisms. A spared nerve injury (SNI) rat model was performed to investigate whether resveratrol could exert anti-mechanical allodynia effects via inhibiting neuroinflammation. To evaluate the role of TREM2 in anti-neuroinflammatory function of resveratrol, lentivirus coding TREM2 was intrathecally injected into SNI rats to activate TREM2, and the pain behavior was detected by the von Frey test. Furthermore, 3-methyladenine (3-MA, an autophagy inhibitor) was applied to study the molecular mechanisms of resveratrol-mediated anti-neuroinflammation using Western blot, qPCR, and immunofluorescence. The TREM2 expression and number of the microglial cells were significantly increased in the ipsilateral spinal dorsal horn after SNI. We found that intrathecal administration of resveratrol (300ug/day) alleviated mechanical allodynia; obviously enhanced autophagy; and markedly reduced the levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α in the ipsilateral spinal dorsal horn after SNI. Moreover, the number of Iba-1+ microglial cells and TREM2 expression were downregulated after resveratrol treatment. Intrathecal administration of lentivirus coding TREM2 and/or 3-MA in those rats induced deficiencies in resveratrol-mediated anti-inflammation, leading to mechanical allodynia that could be rescued via administration of Res. Furthermore, 3-MA treatment contributed to TREM2-mediated mechanical allodynia. Taken together, these data reveal that resveratrol relieves neuropathic pain through suppressing microglia-mediated neuroinflammation via regulating the TREM2-autophagy axis in SNI rats.

中文翻译：

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白藜芦醇通过在 SNI 大鼠模型中通过 TREM2-自噬轴调节炎症反应来介导机械性异常性疼痛

神经性疼痛 (NeuP) 是一种慢性且具有挑战性的临床问题，几乎没有有效的治疗方法。白藜芦醇通过抑制 NeuP 中的炎症反应显示出神经保护作用。最近，小胶质细胞表达的髓样细胞 2 (TREM2) 上表达的触发受体被确定为神经系统疾病炎症的关键因素。在这项研究中，我们探讨了白藜芦醇是否可以通过调节神经损伤大鼠的 TREM2 来改善神经炎症并产生抗机械异常性疼痛作用，并研究其潜在机制。进行了幸免神经损伤（SNI）大鼠模型以研究白藜芦醇是否可以通过抑制神经炎症发挥抗机械异常性疼痛作用。评估TREM2在白藜芦醇抗神经炎症功能中的作用，将编码TREM2的慢病毒鞘内注射到SNI大鼠体内激活TREM2，von Frey试验检测疼痛行为。此外，3-甲基腺嘌呤（3-MA，一种自噬抑制剂）用于使用蛋白质印迹、qPCR 和免疫荧光研究白藜芦醇介导的抗神经炎症的分子机制。SNI后同侧脊髓背角TREM2表达和小胶质细胞数量显着增加。我们发现鞘内注射白藜芦醇（300 微克/天）可减轻机械性异常性疼痛；自噬明显增强；并显着降低SNI后同侧脊髓背角白细胞介素1β、白细胞介素6和肿瘤坏死因子α的水平。此外，白藜芦醇处理后，Iba-1+小胶质细胞数量和TREM2表达下调。在这些大鼠中鞘内注射编码 TREM2 和/或 3-MA 的慢病毒会导致白藜芦醇介导的抗炎作用不足，导致机械性异常性疼痛，可通过注射 Res 来挽救。此外，3-MA 治疗有助于 TREM2 介导的机械性异常性疼痛。总之，这些数据表明，白藜芦醇通过调节 SNI 大鼠的 TREM2-自噬轴来抑制小胶质细胞介导的神经炎症，从而缓解神经性疼痛。3-MA 治疗导致 TREM2 介导的机械性异常性疼痛。总之，这些数据表明，白藜芦醇通过调节 SNI 大鼠的 TREM2-自噬轴来抑制小胶质细胞介导的神经炎症，从而缓解神经性疼痛。3-MA 治疗导致 TREM2 介导的机械性异常性疼痛。总之，这些数据表明，白藜芦醇通过调节 SNI 大鼠的 TREM2-自噬轴来抑制小胶质细胞介导的神经炎症，从而缓解神经性疼痛。