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      Quercetin Alleviates Neuropathic Pain in the Rat CCI Model by Mediating AMPK/MAPK Pathway

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          Abstract

          Context

          Quercetin (que) is one abundant flavonol with a variety of biological activities. Previous studies have shown quercetin can reduce neuropathic pain in rats with chronic constriction injury (CCI).

          Objective

          To evaluate the effects of quercetin on neuropathic pain in CCI model and explore its underlying mechanism in vivo.

          Materials and Methods

          CCI model was established by ligating the sciatic nerve of right leg on the SD rats. They were divided into ten groups: sham group, CCI model, sham+ que, CCI+ que group (30, 60, 120 mg/kg), CCI+ AICAR, CCI+ que+ compound C, CCI+etoricoxib, and the control group. They were administered for 28 days, and were performed the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) during the experiment. At the end of the experiment, sciatic nerves and spinal cord segments of rats were collected, ELISA detected the expression of inflammatory factors, detected the microglia and astrocytes with fluorescence, and Western blot detected AMPK/MAPK pathway.

          Results

          Que could increase the MWT of CCI rats, improve the TWL of plantar, and reduce the inflammatory cells at the ligation site of the sciatic nerve. Also, que could reduce the levels of TNF-α, IL-6, and IL-1β. Western blotting results showed that p-38 MAPK, p-ERK, and p-JNK were activated in the spinal dorsal horn of CCI model group. After treatment with que and AMPK agonists, the phosphorylation levels of related proteins were inhibited. In addition, the analgesic effect of que was abolished when the AMPK inhibitor was added.

          Discussion and Conclusion

          Quercetin alleviated the inflammatory response of sciatic nerve and spinal dorsal horn in rats induced by CCI. Quercetin alleviates neuralgia in CCI rats by activating AMPK pathway and inhibiting MAPK pathway and its downstream targets, p-38, p-ERK, and p-JNK.

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          Most cited references 40

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          A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man

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            Neuron-glia crosstalk gets serious: role in pain hypersensitivity.

             Ronald Dubner,  Ke Ren (2008)
            Recent studies show that peripheral injury activates both neuronal and nonneuronal or glial components of the peripheral and central cellular circuitry. The subsequent neuron-glia interactions contribute to pain hypersensitivity. This review will briefly discuss novel findings that have shed light on the cellular mechanisms of neuron-glia interactions in persistent pain. Two fundamental questions related to neuron-glia interactions in pain mechanisms have been addressed: what are the signals that lead to central glial activation after injury and how do glial cells affect central nervous system neuronal activity and promote hyperalgesia? Evidence indicates that central glial activation depends on nerve inputs from the site of injury and release of chemical mediators. Hematogenous immune cells may migrate to/infiltrate the brain and circulating inflammatory mediators may penetrate the blood-brain barrier to participate in central glial responses to injury. Inflammatory cytokines such as interleukin-1beta released from glia may facilitate pain transmission through its coupling to neuronal glutamate receptors. This bidirectional neuron-glia signaling plays a key role in glial activation, cytokine production and the initiation and maintenance of hyperalgesia. Recognition of the contribution of the mutual neuron-glia interactions to central sensitization and hyperalgesia prompts new treatment for chronic pain.
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              Induction of thermal hyperalgesia and synaptic long-term potentiation in the spinal cord lamina I by TNF-α and IL-1β is mediated by glial cells.

              Long-term potentiation (LTP) of synaptic strength in nociceptive pathways is a cellular model of hyperalgesia. The emerging literature suggests a role for cytokines released by spinal glial cells for both LTP and hyperalgesia. However, the underlying mechanisms are still not fully understood. In rat lumbar spinal cord slices, we now demonstrate that conditioning high-frequency stimulation of primary afferents activated spinal microglia within <30 min and spinal astrocytes within ~2 s. Activation of spinal glia was indispensible for LTP induction at C-fiber synapses with spinal lamina I neurons. The cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), which are both released by activated glial cells, were individually sufficient and necessary for LTP induction via redundant pathways. They differentially amplified 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)-propanoic acid receptor-mediated and N-methyl-D-aspartic acid receptor-mediated synaptic currents in lamina I neurons. Unexpectedly, the synaptic effects by IL-1β and TNF-α were not mediated directly via activation of neuronal cytokine receptors, but rather, indirectly via IL-1 receptors and TNF receptors being expressed on glial cells in superficial spinal dorsal horn. Bath application of IL-1β or TNF-α led to the release profiles of pro-inflammatory and anti-inflammatory cytokines, chemokines, and growth factors, which overlapped only partially. Heat hyperalgesia induced by spinal application of either IL-1β or TNF-α in naive animals also required activation of spinal glial cells. These results reveal a novel, decisive role of spinal glial cells for the synaptic effects of IL-1β and TNF-α and for some forms of hyperalgesia.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                jpr
                jpainres
                Journal of Pain Research
                Dove
                1178-7090
                19 May 2021
                2021
                : 14
                : 1289-1301
                Affiliations
                [1 ]Department of Anesthesiology, Ningbo No.6 Hospital , Ningbo, 315040, People’s Republic of China
                [2 ]School of Medicine, Ningbo University , Ningbo, 315211, People’s Republic of China
                [3 ]Department of Anesthesiology and Pharmacology, Xuzhou Medical University , Xuzhou, 221000, People’s Republic of China
                Author notes
                Correspondence: Liyong Yuan Department of Anesthesiology, Ningbo No.6 Hospital , Ningbo, 315040, People’s Republic of China Email yuanl1973@yeah.net
                Tao Ma Department of Anesthesiology and Pharmacology, Xuzhou Medical University , Xuzhou, 221000, People’s Republic of China Email Matao201006@126.com
                [*]

                These authors contributed equally to this work

                Article
                298727
                10.2147/JPR.S298727
                8141401
                34040433
                © 2021 Ye 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, References: 40, Pages: 13
                Categories
                Original Research

                Anesthesiology & Pain management

                neuropathic pain, quercetin, ampk, mapk, cci

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