目的·探讨转位分子蛋白（translocator protein，TSPO）激动剂Ro5-4864对糖尿病神经病理性疼痛（diabetic neuropathic pain，DNP）大鼠坐骨神经自噬和Kelch样ECH关联蛋白（Kelch-like ECH-associated protein 1，Keap1）/核因子E2 相关因子（nuclear factor erythroid-derived-2-like 2，Nrf2）/血红素加氧酶-1（heme oxygenase-1，HO-1）通路的影响。方法·通过高脂饮食和链脲佐菌素构建2型糖尿病模型，经行为学筛选获得DNP大鼠。24只大鼠根据数字表随机分配到假手术组（Sham组）、DNP模型组（DNP组）、TSPO激动剂Ro5-4864处理组（Ro组）和TSPO激动剂Ro5-4864合用Nrf2抑制剂ML385处理组（Ro+ML385组）。采用up-down法测量大鼠50%机械缩足反射阈值（paw 50% mechanical withdrawal threshold，50% PMWT），时间点选定为处理前（baseline），处理后第3（D3）、7（D7）、14（D14）、21（D21）和28（D28）天。在最后1天收集坐骨神经，使用免疫荧光和Western blotting分析鞘内注射Ro5-4864对DNP大鼠坐骨神经中自噬相关蛋白和Keap1/Nrf2/HO-1通路相关蛋白的影响。结果·与Sham组相比，DNP组大鼠的50% PMWT自第3天开始大幅下降，全程无改善（各时间点均P=0.000）；另外，DNP大鼠坐骨神经中Bcl-2相互作用蛋白（Bcl-2 interacting coiled-coil protein 1，Beclin-1）、微管相关蛋白轻链3-Ⅱ（microtubule-associated protein light chain 3-Ⅱ，LC3-Ⅱ）、HO-1和核Nrf2蛋白的含量显著减少（均P=0.000），p62则显著增加（P=0.000）。鞘内注射Ro5-4864改善了以上损伤，大鼠50% PMWT与DNP组相比逐渐上升（D14 P=0.039，D21和D28均P=0.000），自噬和Keap1/Nrf2/HO-1通路的损伤也被修复，表现为Beclin-1、LC3-Ⅱ、HO-1和核Nrf2蛋白含量的升高（均P=0.000）以及p62含量的降低（P=0.001）。但是，Ro5-4864的效应被ML385完全抑制。结论·TSPO激动剂Ro5-4864缓解了DNP，其作用机制可能与通过对Keap1/Nrf2/HO-1通路的正向调节激活了DNP大鼠坐骨神经中的自噬相关。这可能为治疗DNP提供了一个新的策略。

Objective ·To study the effects of translocator protein (TSPO) agonist Ro5-4864 on autophagy and Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid-derived-2-like 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling in diabetic neuropathic pain (DNP) rats. Methods ·Type 2 diabetic rats were established by high-fat diet and streptozotocin (STZ), and DNP rats were filtered by behavioral assessment. Twenty-four rats were randomly assigned to the Sham group, DNP group, TSPO agonist Ro5-4864 group (Ro group), and TSPO agonist Ro5-4864 combined with Nrf2 inhibitor ML385 group (Ro+ML385 group). Up-Down method was used to measure paw 50% mechanical withdrawal threshold (50% PMWT) of the rats before high-fat diet (baseline), and on Day 3, 7, 14, 21 and 28 after STZ. Sciatic nerves were collected on the last day to analyze the effects of Ro5-4864 on autophagy related proteins and Keap1/Nrf2/HO-1 signaling related proteins of DNP rats by using immunofluorescence and Western blotting. Results ·The 50% PMWT in the DNP group decreased from D3 to D28 (P=0.000 at all timing), and the expression of Bcl-2 interacting coiled-coil protein 1 (Beclin-1), microtubule-associated protein light chain 3-Ⅱ (LC3-Ⅱ), HO-1, and nuclear Nrf2 (P=0.000) were significantly reduced in the sciatic nerves of DNP rats (all P=0.000), compared with those in the sham group, but p62 was significantly increased (P=0.000). Administration of Ro5-4864 attenuated these changes in the rats of the Ro group. There was a gradual increase in the 50% PMWT, compared with that of the rats in the DNP group (D14 P=0.039, both D21 and D28 P=0.000), and the impairment of autophagy and the Keap1/Nrf2/HO-1 signaling was repaired, which was demonstrated by increases of Beclin-1, LC3-Ⅱ, HO-1, and nuclear Nrf2 protein contents (all P=0.000) and a decrease in p62 content (P=0.001). However, the beneficial effects of Ro5-4864 were totally abrogated by ML385 in rats of the Ro+ML385 group. Conclusion ·TSPO alleviates DNP in rats, of which the mechanism involves activation of autophagy via upregulation of the Keap1/Nrf2/HO-1 signaling in sciatic nerves. This study provides a new strategy for the treatment of DNP.