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Our previous work showed that spared nerve injury (SNI) that induces neuropathic pain causes short-term memory deficits. Here, we reported that GSK-3\u03b2 activity was enhanced in hippocampus and reduced in spinal dorsal horn following SNI, and the changes persisted for at least 45 days. Repetitive applications of selective GSK-3\u03b2 inhibitors (SB216763, 5\u2009mg\/kg, intraperitoneally, three times or AR-A014418, 400\u2009ng\/kg, intrathecally, seven times) prevented short-term memory deficits but did not affect neuropathic pain induced by SNI. Surprisingly, we found that the repetitive SB216763 or AR-A014418 induced a persistent pain hypersensitivity in sham animals. Mechanistically, both \u03b2-catenin and brain-derived neurotrophic factor (BDNF) were upregulated in spinal dorsal horn but downregulated in hippocampus following SNI. Injections of SB216763 prevented the BDNF downregulation in hippocampus but enhanced its upregulation in spinal dorsal horn in SNI rats. In sham rats, SB216763 upregulated both \u03b2-catenin and BDNF in spinal dorsal horn but affect neither of them in hippocampus. Finally, intravenous injection of interleukin-1beta that induces pain hypersensitivity and memory deficits mimicked the SNI-induced the differential regulation of GSK-3\u03b2\/\u03b2-catenin\/BDNF in spinal dorsal horn and in hippocampus. Accordingly, the prolonged opposite changes of GSK-3\u03b2 activity in hippocampus and in spinal dorsal horn induced by SNI may contribute to memory deficits and neuropathic pain by differential regulation of BDNF in the two regions. GSK-3\u03b2 inhibitors that treat cognitive disorders may result in a long-lasting pain hypersensitivity.<\/jats:p>","DOI":"10.1177\/1744806919826789","type":"journal-article","created":{"date-parts":[[2019,1,11]],"date-time":"2019-01-11T06:55:35Z","timestamp":1547189735000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":26,"title":["Differential regulation of GSK-3\u03b2 in spinal dorsal horn and in hippocampus mediated by interleukin-1beta contributes to pain hypersensitivity and memory deficits following peripheral nerve injury"],"prefix":"10.1177","volume":"15","author":[{"given":"Chun-Lin","family":"Mai","sequence":"first","affiliation":[{"name":"Pain Research Center and Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Wei","sequence":"additional","affiliation":[{"name":"Pain 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