title: Glycogen synthase kinase-3β contributes to remifentanil-induced postoperative hyperalgesia via regulating N-methyl-D-aspartate receptor trafficking.
abstract: BACKGROUND
  Although remifentanil provides perfect analgesia during surgery, postoperative hyperalgesia after remifentanil administration might be a challenge to anesthesiologists. The trafficking and activation of N-methyl-D-aspartate (NMDA) receptors have a pivotal role in the development and maintenance of remifentanil-induced postoperative hyperalgesia. However, the underlying mechanisms of hyperalgesia are poorly elucidated. We designed the present study to examine the hypothesis that glycogen synthase kinase (GSK)-3β could contribute to remifentanil-induced postoperative hyperalgesia via regulating NMDA receptor trafficking in the spinal cord.
  
  
  METHODS
  Using a rat model of remifentanil-induced postoperative hyperalgesia, we first tested thermal and mechanical hyperalgesia at baseline (24 hours before incision) and 2, 6, 24, and 48 hours after remifentanil infusion. GSK-3β mRNA and protein expression and NMDA receptor subunits (NR1, NR2A, and NR2B) trafficking in the spinal cord L4-L6 segments were then measured using real-time polymerase chain reaction and Western blot analysis. Furthermore, we investigated the effects of TDZD-8, a selective GSK-3β inhibitor, on remifentanil-induced postoperative hyperalgesia and NMDA receptor subunits trafficking.
  
  
  RESULTS
  Remifentanil induced significant postoperative hyperalgesia, as indicated by increased paw withdrawal latencies and thresholds to thermal and mechanical stimulation, which were markedly improved by pretreatment with TDZD-8. Moreover, remifentanil infusion increased the expression of GSK-3β mRNA and protein as well as the GSK-3β activity in the spinal cord. More importantly, intraoperative infusion of remifentanil increased NMDA receptor subunits (NR1 and NR2B) trafficking from the intracellular pool to surface pool in the spinal cord, which was significantly attenuated by TDZD-8.
  
  
  CONCLUSIONS
  The above results suggest that activation of GSK-3β contributes to remifentanil-induced postoperative hyperalgesia via regulating NMDA receptor subunits (NR1 and NR2B) trafficking in the spinal cord. Inhibition of GSK-3β may be an effective novel option for the treatment of remifentanil-induced postoperative hyperalgesia.
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Jing-yao
authors.initials: JY
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.forename: Ke-liang
authors.initials: KL
authors.lastname: Xie
authors.forename: Yong-hao
authors.initials: YH
authors.lastname: Yu
authors.forename: Guo-lin
authors.initials: GL
authors.lastname: Wang
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects*; D000818:Animals; D015153:Blotting, Western; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D010149:Postoperative Pain / Q000139:chemically induced* / Q000378:metabolism; D010812:Physical Stimulation; D010880:Piperidines / Q000009:adverse effects*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D000077208:Remifentanil; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology
chemical_list: C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D000701:Analgesics, Opioid; D010880:Piperidines; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D013830:Thiadiazoles; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D000077208:Remifentanil