Differential regulation of GSK-3β in spinal dorsal horn and in hippocampus mediated by interleukin-1beta contributes to pain hypersensitivity and memory deficits following peripheral nerve injury

Accumulating evidence shows that inhibition of glycogen synthase kinase-3beta (GSK-3β) ameliorates cognitive impairments caused by a diverse array of diseases. Our previous work show that spared nerve injury (SNI) that induces neuropathic pain causes short-term memory (STM) deficits.Here,we reported that GSK-3β activity was enhanced in hippocampus and reduced in spinal dorsal horn following SNI, and the changes persisted for at least 45 d. Repetitive applications of selective GSK-3β inhibitors (SB216763, 5 mg/kg, i.p., 3 times or AR-A014418, 400 ng/kg, i.t., 7 times) prevented STM deficits but did not affect neuropathic pain in SNI rats. Surprisingly, we found that the repetitive SB216763 or AR-A014418 induced a persistent pain hypersensitivity in sham animals. Mechanistically,both β-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 ...