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

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          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 NR 2B 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 NR 2B 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 NR 2B subunit, c-fos, NF-κB, β-catenin, wnt3a and p-GSK-3β (Ser9) were detected in the lumbar spinal cord.


          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 NR 2B subunit antagonist Ro25-6981 and iwp-2 decreased the amount of activated NR 2B, 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).


          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, NR 2B in spinal dorsal horn.

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          Most cited references 34

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          Central mechanisms of pathological pain.

           Rohini Kuner (2010)
          Chronic pain is a major challenge to clinical practice and basic science. The peripheral and central neural networks that mediate nociception show extensive plasticity in pathological disease states. Disease-induced plasticity can occur at both structural and functional levels and is manifest as changes in individual molecules, synapses, cellular function and network activity. Recent work has yielded a better understanding of communication within the neural matrix of physiological pain and has also brought important advances in concepts of injury-induced hyperalgesia and tactile allodynia and how these might contribute to the complex, multidimensional state of chronic pain. This review focuses on the molecular determinants of network plasticity in the central nervous system (CNS) and discusses their relevance to the development of new therapeutic approaches.
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            LTP inhibits LTD in the hippocampus via regulation of GSK3beta.

            Glycogen synthase kinase-3 (GSK3) has been implicated in major neurological disorders, but its role in normal neuronal function is largely unknown. Here we show that GSK3beta mediates an interaction between two major forms of synaptic plasticity in the brain, N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) and NMDA receptor-dependent long-term depression (LTD). In rat hippocampal slices, GSK3beta inhibitors block the induction of LTD. Furthermore, the activity of GSK3beta is enhanced during LTD via activation of PP1. Conversely, following the induction of LTP, there is inhibition of GSK3beta activity. This regulation of GSK3beta during LTP involves activation of NMDA receptors and the PI3K-Akt pathway and disrupts the ability of synapses to undergo LTD for up to 1 hr. We conclude that the regulation of GSK3beta activity provides a powerful mechanism to preserve information encoded during LTP from erasure by subsequent LTD, perhaps thereby permitting the initial consolidation of learnt information.
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              Opioid-induced hyperalgesia: a qualitative systematic review.

              Opioids are the cornerstone therapy for the treatment of moderate to severe pain. Although common concerns regarding the use of opioids include the potential for detrimental side effects, physical dependence, and addiction, accumulating evidence suggests that opioids may yet cause another problem, often referred to as opioid-induced hyperalgesia. Somewhat paradoxically, opioid therapy aiming at alleviating pain may render patients more sensitive to pain and potentially may aggravate their preexisting pain. This review provides a comprehensive summary of basic and clinical research concerning opioid-induced hyperalgesia, suggests a framework for organizing pertinent information, delineates the status quo of our knowledge, identifies potential clinical implications, and discusses future research directions.

                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                19 May 2020
                : 13
                : 1049-1058
                [1 ]Department of Anesthesiology, 1st Affiliated Hospital, Wenzhou Medical University , Wenzhou, Zhejiang, People’s Republic of China
                Author notes
                Correspondence: Jiehao Sun Shangcai Cun 1#, Ouhai District, Wenzhou325000, People’s Republic of ChinaTel +86-13676721930Fax +86-577-88513632 Email sun_jiehao@126.com

                These authors contributed equally to this work

                © 2020 Gao et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 5, Tables: 1, References: 34, Pages: 10
                Funded by: Chinese National Natural Science
                Award ID: 81701094
                Funded by: Zhejiang Provincial Natural Science Funding
                Award ID: LY20H090008
                Funded by: Wenzhou Science and Technology Bureau
                Award ID: Y20180121
                This work was supported by the Chinese National Natural Science Funding [81701094]; Zhejiang Provincial Natural Science Funding [LY20H090008] and Wenzhou Science and Technology Bureau [Y20180121].
                Original Research

                Anesthesiology & Pain management

                remifentanil, hyperalgesia, iwp-2, nr2b, wnt3a/β-catenin


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