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Neuropathic pain is a debilitating disease with few effective treatments. Emerging evidence indicates the involvement of mitochondrial dysfunction and oxidative stress in neuropathic pain. Nuclear factor erythroid 2\u2010related factor 2 (Nrf2) is a potent regulator of the antioxidant response system. In this study, we investigated whether RTA\u2010408 (RTA, a novel synthetic triterpenoid under clinical investigation) could activate Nrf2 and promote mitochondrial biogenesis (MB) to reverse neuropathic pain and the underlying mechanisms. <jats:italic>Methods<\/jats:italic>. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Pain behaviors were measured via the von Frey test and Hargreaves plantar test. The L4\u20106 spinal cord was collected to examine the activation of Nrf2 and MB. <jats:italic>Results<\/jats:italic>. RTA\u2010408 treatment significantly reversed mechanical allodynia and thermal hyperalgesia in CCI mice in a dose\u2010dependent manner. Furthermore, RTA\u2010408 increased the activity of Nrf2 and significantly restored MB that was impaired in CCI mice in an Nrf2\u2010dependent manner. Peroxisome proliferator\u2010activated receptor\u2010gamma coactivator\u20101alpha (PGC\u20101<jats:italic>\u03b1<\/jats:italic>) is the key regulator of MB. We found that the PGC\u20101<jats:italic>\u03b1<\/jats:italic> activator also induced a potent analgesic effect in CCI mice. Moreover, the antinociceptive effect of RTA\u2010408 was reversed by the preinjection of the PGC\u20101<jats:italic>\u03b1<\/jats:italic> inhibitor. <jats:italic>Conclusions<\/jats:italic>. Nrf2 activation attenuates chronic constriction injury\u2010induced neuropathic pain via induction of PGC\u20101<jats:italic>\u03b1<\/jats:italic>\u2010mediated mitochondrial biogenesis in the spinal cord. Our results indicate that Nrf2 may be a potential therapeutic strategy to ameliorate neuropathic pain and many other disorders with oxidative stress and mitochondrial dysfunction.<\/jats:p>","DOI":"10.1155\/2021\/9577874","type":"journal-article","created":{"date-parts":[[2021,10,22]],"date-time":"2021-10-22T02:22:07Z","timestamp":1634869327000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Nrf2 Activation Attenuates Chronic Constriction Injury\u2010Induced Neuropathic Pain via Induction of PGC\u20101<i>\u03b1<\/i>\u2010Mediated Mitochondrial Biogenesis in the Spinal Cord"],"prefix":"10.1155","volume":"2021","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3595-8932","authenticated-orcid":false,"given":"Jia","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1626-1964","authenticated-orcid":false,"given":"Jia-Yan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9396-3778","authenticated-orcid":false,"given":"Long-Qing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan-Yang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4214-9028","authenticated-orcid":false,"given":"Jia-Yi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5999-3535","authenticated-orcid":false,"given":"Shao-Jie","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8878-8485","authenticated-orcid":false,"given":"Dai-Qiang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6917-4808","authenticated-orcid":false,"given":"Ya-Qun","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6556-6628","authenticated-orcid":false,"given":"Wei","family":"Mei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,10,21]]},"reference":[{"key":"e_1_2_11_1_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000282763.29778.59"},{"key":"e_1_2_11_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2011.06.017"},{"key":"e_1_2_11_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aen107"},{"key":"e_1_2_11_4_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.117.243048"},{"key":"e_1_2_11_5_2","article-title":"Pharmacological inhibition of the nlrp3 in flammasome as a potential target for cancer-induced bone pain","volume":"147","author":"Chen S. 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