神经病理性疼痛发病率高，疗效不佳，发病机制不清。转录因子NRF2具有抗炎、抗氧化应激和神经保护作用，参与炎性疼痛调控，但NRF2是否调控神经病理性疼痛尚不明确。研究发现自噬底物蛋白P62调控NRF2活化，发挥抗氧化应激作用，鉴于P62蛋白与自噬过程密切相关，提示自噬可能调控NRF2活化。我们预实验结果发现脊神经结扎后，小鼠疼痛阈值降低，脊髓自噬水平减弱，NRF2总蛋白表达及核转移增加；鞘内注射自噬抑制剂抑制自噬，NRF2总蛋白表达及核转移较对照组显著增加，炎性因子表达降低；利用NRF2敲除小鼠行脊神经结扎，其疼痛阈值较野生型小鼠降低而炎性因子表达增加。因此，我们推测自噬可能通过影响NRF2通路的活化来调控神经病理性疼痛。本项目中，我们将利用NRF2基因敲除小鼠来系统研究自噬-NRF2通路调控神经病理性疼痛的作用及具体分子信号机制，为神经病理性疼痛的发生发展提供新的机制解说和潜在治疗靶点。

Neuropathic pain has high morbidity and low cure rates, while the pathogenesis of neuropathic pain remains obscure. Transcription factor NRF2 has antinociceptive effects against inflammatory pain due to its role of anti-inflammation and anti-oxidative stress. However, little is known about whether NRF2 regulates neuropathic pain. Some studies have found that autophagy-adaptor protein P62 promotes nuclear translocation of NRF2 and induces expression of NRF2 targets. These studies prompt that autophagy might regulate activation of NRF2 signaling. In our preliminary study, we found that the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were significantly decreased after spinal nerve ligation (SNL), and these change were accompanied by inhibited autophagy and increased protein level and nuclear translocation of NRF2 in the ipsilateral spinal cord. Inhibition of autophagy with 3-MA, a widely used autophagy inhibitor, could further increase the expression and nuclear translocation of NRF2 and reduce the production of inflammatory cytokines. Moreover, both PWT and PWL of NRF2 knockout mice were less than the WT mice’s after SNL, while the expression of inflammatory cytokines was increased. Therefore, we hypothesized that autophagy may regulate neuropathic pain by affecting the activation of NRF2 pathway. In this project, we will study the role and the molecular mechanism of autophagy-NRF2 pathway in the development of neuropathic pain with the NRF2 knockout mice, which may provide a new mechanism hypothesis and a potential therapeutic target of neuropathic pain.