title: Inhibition of glycogen synthase kinase-3β prevents remifentanil-induced hyperalgesia via regulating the expression and function of spinal N-methyl-D-aspartate receptors in vivo and vitro.
abstract: A large number of experimental and clinical studies have confirmed that brief remifentanil exposure can enhance pain sensitivity presenting as opioid-induced hyperalgesia (OIH). N-methyl-D-aspartate (NMDA) receptor antagonists have been reported to inhibit morphine analgesic tolerance in many studies. Recently, we found that glycogen synthase kinase-3β (GSK-3β) modulated NMDA receptor trafficking in a rat model of remifentanil-induced postoperative hyperalgesia. In the current study, it was demonstrated that GSK-3β inhibition prevented remifentanil-induced hyperalgesia via regulating the expression and function of spinal NMDA receptors in vivo and in vitro. We firstly investigated the effects of TDZD-8, a selective GSK-3β inhibitor, on thermal and mechanical hyperalgesia using a rat model of remifentanil-induced hyperalgesia. GSK-3β activity as well as NMDA receptor subunits (NR1, NR2A and NR2B) expression and trafficking in spinal cord L4-L5 segments were measured by Western blot analysis. Furthermore, the effects of GSK-3β inhibition on NMDA-induced current amplitude and frequency were studied in spinal cord slices by whole-cell patch-clamp recording. We found that remifentanil infusion at 1 μg·kg(-1)·min(-1) and 2 μg·kg(-1)·min(-1) caused mechanical and thermal hyperalgesia, up-regulated NMDA receptor subunits NR1 and NR2B expression in both membrane fraction and total lysate of the spinal cord dorsal horn and increased GSK-3β activity in spinal cord dorsal horn. GSK-3β inhibitor TDZD-8 significantly attenuated remifentanil-induced mechanical and thermal hyperalgesia from 2 h to 48 h after infusion, and this was associated with reversal of up-regulated NR1 and NR2B subunits in both membrane fraction and total lysate. Furthermore, remifentanil incubation increased amplitude and frequency of NMDA receptor-induced current in dorsal horn neurons, which was prevented with the application of TDZD-8. These results suggest that inhibition of GSK-3β can significantly ameliorate remifentanil-induced hyperalgesia via modulating the expression and function of NMDA receptors, which present useful insights into the mechanistic action of GSK-3β inhibitor as potential anti-hyperalgesic agents for treating OIH.
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, P. R. China ; Tianjin Research Institute of Anesthesiology, Tianjin, P. R. China.
authors.forename: Yize
authors.initials: Y
authors.lastname: Li
authors.forename: Haiyun
authors.initials: H
authors.lastname: Wang
authors.forename: Keliang
authors.initials: K
authors.lastname: Xie
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wang
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Yang
authors.forename: Yonghao
authors.initials: Y
authors.lastname: Yu
authors.forename: Guolin
authors.initials: G
authors.lastname: Wang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced* / Q000201:enzymology*; D008297:Male; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000009:adverse effects*; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D000077208:Remifentanil; D013131:Spine / Q000187:drug effects / Q000378:metabolism
chemical_list: D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D038362:Glycogen Synthase Kinase 3; D000077208:Remifentanil