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

BACKGROUND: Many studies have confirmed that brief remifentanil exposure can enhance pain sensitivity. We previously reported that activation of glycogen synthase kinase-3 beta (GSK-3 beta) 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-3 beta inhibition prevented remifentanil-induced postoperative hyperalgesia via regulating a-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-3 beta activity in the spinal dorsal horn. Furthermore, whole-cell patch-clamp recording was used to analyze the effect of GSK-3 beta 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-3 beta inhibitors, LiCl and TDZD, treatment ameliorates remifentanilinduced 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-3 beta 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.