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Stimulated neuroinflammation and elevated mitochondrial oxidative stress are associated arthritis pain. In the present study, arthritis model was established by intra-articular injection of complete Freund\u2019s adjuvant (CFA) on mice. Knee swelling, pain hypersensitivity and motor disability were observed in CFA-induced mice. In spinal cord, neuroinflammation was triggered and presented as severe infiltration of inflammatory cells and up-regulated expressions of glial fibrillary acidic protein (GFAP), nuclear factor-kappaB (NF-\u03baB), PYD domains-containing protein 3 (NLRP3), cysteinyl aspartate specific proteinase (caspase-1) and interleukin-1 beta (IL-1\u03b2). Mitochondrial function was disrupted and characterized as elevated expressions of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), dihydroorotate dehydrogenase (DHODH) and cytochrome C (Cyto C), and reduced expressions of Bcl-2 and Mn-superoxide dismutase (Mn-SOD) activity. Meanwhile, as a potential target for pain management, glycogen synthase kinase-3 beta (GSK-3\u03b2) activity was up-regulated in CFA induced mice. To explore potential therapeutic options for arthritis pain, GSK-3\u03b2 inhibitor TDZD-8 was intraperitoneally injected for three days on CFA mice. Animal behavioral tests found that TDZD-8 treatment elevated mechanical pain sensitivity, suppressed spontaneous pain and recovered motor coordination. Morphological and protein expression analysis indicated that TDZD-8 treatment decreased spinal inflammation score and inflammatory related protein levels, recovered mitochondrial related protein levels, and increased Mn-SOD activity. In summary, TDZD-8 treatment inhibits GSK-3\u03b2 activity, reduces mitochondrial mediated oxidative stress, suppresses spinal inflammasome response, and alleviates arthritis pain.<\/jats:p>","DOI":"10.1371\/journal.pone.0284332","type":"journal-article","created":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T17:30:33Z","timestamp":1681493433000},"page":"e0284332","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["GSK-3\u03b2 inhibition alleviates arthritis pain via reducing spinal mitochondrial reactive oxygen species level and inflammation"],"prefix":"10.1371","volume":"18","author":[{"given":"He-Yu","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Qing","family":"Zhen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang-Zhu","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie-Qiong","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7802-676X","authenticated-orcid":true,"given":"Hai-Li","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,4,14]]},"reference":[{"issue":"10182","key":"pone.0284332.ref001","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1016\/S0140-6736(19)30417-9","article-title":"Osteoarthritis","volume":"393","author":"DJ Hunter","year":"2019","journal-title":"Lancet"},{"issue":"9","key":"pone.0284332.ref002","doi-asserted-by":"crossref","first-page":"4642","DOI":"10.3390\/ijms23094642","article-title":"Osteoarthritis Pain","volume":"23","author":"H Yu","year":"2022","journal-title":"Int J Mol Sci"},{"issue":"4","key":"pone.0284332.ref003","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.joca.2021.11.018","article-title":"Working toward mechanistic pain phenotyping in osteoarthritis","volume":"30","author":"JA Crow","year":"2022","journal-title":"Osteoarthritis Cartilage"},{"issue":"4","key":"pone.0284332.ref004","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.jbspin.2017.08.002","article-title":"Pain in osteoarthritis. 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