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Wnt3a Inhibitor Attenuates Remifentanil-Induced Hyperalgesia via Downregulating Spinal NMDA Receptor in Rats

Authors Gao Y, Zhou S, Pan Y, Gu L, He Y, Sun J

Received 21 February 2020

Accepted for publication 30 April 2020

Published 19 May 2020 Volume 2020:13 Pages 1049—1058

DOI https://doi.org/10.2147/JPR.S250663

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Robert B. Raffa


Yuan Gao,* Songyi Zhou,* Yizhao Pan, Lijun Gu, Yuting He, Jiehao Sun

Department of Anesthesiology, 1st Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Jiehao Sun Shangcai Cun 1#, Ouhai District, Wenzhou 325000, People’s Republic of China
Tel +86-13676721930
Fax +86-577-88513632
Email sun_jiehao@126.com

Purpose: The upregulation of spinal NMDA receptor is a crucial mechanism in remifentanil-induced hyperalgesia (RIH). Wnt3a/β-catenin pathway plays an important role in neuropathic pain. We hypothesized that wnt3a inhibitor (iwp-2) could downregulate the expression of NR2B subunit in NMDA receptor, in order to relieve RIH.
Materials and Methods: The study has 2 phases. The phase 1 study is designed by different doses of iwp-2 groups to create an appropriate iwp-2 dose used in RIH alleviation. The phase 2 study is designed to prove that the wnt3a inhibitor could downregulate the activation of the NR2B to inhibit RIH in rats. Thermal hyperalgesia (PWTL) and mechanical allodynia (PWMT) were evaluated after RIH. The area under the PWTL and PWMT curves (AUC) were calculated. The amount of activated NR2B subunit, c-fos, NF-κB, β-catenin, wnt3a and p-GSK-3β (Ser9) were detected in the lumbar spinal cord.
Results: Remifentanil infusion could induce overexpression of β-catenin and wnt3a in rats. Iwp-2 (60μM, 120μM, 180μM) could dose-dependently inhibit thermal hyperalgesia and mechanical allodynia in rats. In phase 2 study, both NR2B subunit antagonist Ro25-6981 and iwp-2 decreased the amount of activated NR2B, enhanced p-GSK-3β (Ser9), reduced β-catenin, c-fos and NF-κB in the lumbar spinal cord (p < 0.001). In comparison with the group iwp-2, the group of Ro25-6981 had more benefit in reversing hyperalgesia, including higher AUC value of PWTL (p = 0.022) and PWMT (p = 0.035).
Conclusion: Remifentanil exposure could induce overexpression of wnt3a and enhance the production of β-catenin in the spinal dorsal horn. Inhibition of wnt3a response was capable of attenuating RIH in alleviating hyperalgesia-related behavioral parameters, as well as reducing overexpression of c-fos, NF-κB, NR2B in spinal dorsal horn.

Keywords: remifentanil, hyperalgesia, iwp-2, NR2B, wnt3a/β-catenin

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