title: Glycogen synthase kinase-3β inhibition prevents remifentanil-induced postoperative hyperalgesia via regulating the expression and function of AMPA receptors.
abstract: BACKGROUND
  Many studies have confirmed that brief remifentanil exposure can enhance pain sensitivity. We previously reported that activation of glycogen synthase kinase-3β (GSK-3β) contributes to remifentanil-induced hyperalgesia via regulating N-methyl-D-aspartate receptor plasticity in the spinal dorsal horn. In this study, we demonstrated that GSK-3β inhibition prevented remifentanil-induced postoperative hyperalgesia via regulating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) expression and function in the spinal dorsal horn.
  
  
  METHODS
  Using a rat model of remifentanil-induced incision hyperalgesia, mechanical and thermal pain was tested 1 day before infusion and 2 hours, 6 hours, 1 day, 2 days, 3 days, 5 days, and 7 days after infusion. Western blot analysis was used to detect AMPAR subunit (GluR1 and GluR2) trafficking, AMPAR phosphorylation status, and GSK-3β activity in the spinal dorsal horn. Furthermore, whole-cell patch-clamp recording was used to analyze the effect of GSK-3β inhibition on AMPAR-induced current in the spinal dorsal horn.
  
  
  RESULTS
  Membrane AMPAR subunit GluR1 was upregulated in the spinal cord in remifentanil-induced postoperative hyperalgesia rats (275 ± 36.54 [mean ± SD] vs 100 ± 9.53, P = 0.0009). Selective GSK-3β inhibitors, LiCl and TDZD, treatment ameliorates remifentanil-induced postoperative hyperalgesia, and this was associated with the downregulated GluR1 subunit in the membrane fraction (254 ± 23.51 vs 119 ± 14.74, P = 0.0027; 254 ± 23.51 vs 124 ± 9.35, P = 0.0032). Moreover, remifentanil incubation increased the amplitude and the frequency of AMPAR-induced current in dorsal horn neurons (61.09 ± 9.34 pA vs 32.56 ± 6.44 pA, P = 0.0009; 118.32 ± 20.33 milliseconds vs 643.67 ± 43.29 milliseconds, P = 0.0002), which was prevented with the application of LiCl and TDZD, respectively. Remifentanil-induced postoperative pain induced an increase in pGluR1 Ser845 and Rab5, which was prevented with the application of LiCl and TDZD.
  
  
  CONCLUSIONS
  These results indicate that amelioration of remifentanil-induced postoperative hyperalgesia by GSK-3β inhibition is attributed to downregulated AMPAR GluR1 expression in the membrane fraction and inhibition of AMPAR function via altering pGluR1 and Rab5 expression in the spinal dorsal horn.
authors.affiliation: From the Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin Research Institute of Anesthesiology, Tianjin, China.
authors.forename: Yi-Ze
authors.initials: YZ
authors.lastname: Li
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Tang
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Wang
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.forename: Ke-Liang
authors.initials: KL
authors.lastname: Xie
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Wang
authors.forename: Yong-Hao
authors.initials: YH
authors.lastname: Yu
authors.forename: Guo-Lin
authors.initials: GL
authors.lastname: Wang
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D009924:Organ Culture Techniques; D010149:Postoperative Pain / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D010880:Piperidines / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000077208:Remifentanil
chemical_list: D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D010880:Piperidines; D018091:Receptors, AMPA; D000077208:Remifentanil; C000605508:Gsk3b protein, rat