Glycogen Synthase Kinase-3β Inhibition Prevents Remifentanil-Induced Postoperative Hyperalgesia via Regulating the Expression and Function of AMPA Receptors

• Published in: Anesthesia and analgesia Vol. 119; no. 4; pp. 978 - 987
• Main Authors: Li, Yi-ze, Tang, Xiao-hong, Wang, Chun-yan, Hu, Nan, Xie, Ke-liang, Wang, Hai-yun, Yu, Yong-hao, Wang, Guo-lin
• Format: Journal Article
• Language: English
• Published: United States International Anesthesia Research Society 01.10.2014
• Subjects: Animals; Enzyme Inhibitors - pharmacology; Gene Expression Regulation; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Hyperalgesia - chemically induced; Hyperalgesia - metabolism; Hyperalgesia - prevention & control; Male; Organ Culture Techniques; Pain, Postoperative - chemically induced; Pain, Postoperative - metabolism; Pain, Postoperative - prevention & control; Piperidines - adverse effects; Piperidines - antagonists & inhibitors; Posterior Horn Cells - drug effects; Posterior Horn Cells - metabolism; Rats; Rats, Sprague-Dawley; Receptors, AMPA - antagonists & inhibitors; Receptors, AMPA - biosynthesis
• ISSN: 0003-2999; 1526-7598
• DOI: 10.1213/ANE.0000000000000365

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.