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      Hyperbaric oxygen relieves neuropathic pain through AKT/TSC2/mTOR pathway activity to induce autophagy

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          Our previous study suggested that HBO treatment attenuated neuropathic pain by inhibiting mTOR to induce autophagy in SNL neuropathic pain model. The aim of this study was to evaluate the role of AKT/TSC2/mTOR pathway in SNL and autophagy and determine whether HBO treatment could relieve neuropathic pain via modulating AKT/TSC2/mTOR pathway.

          Materials and methods

          Rats were randomly divided into sham, SNL, SNL + HBO treatment, SNL + vehicle, and SNL + AKT inhibitor groups. Neuropathic pain was induced following SNL procedure. Rats in the SNL + HBO group received HBO treatment for 7 consecutive days beginning on postoperative day 1. The SNL + vehicle group received 10 µL of 3% dimethyl sulfoxide in saline. SNL + AKT inhibitor group received 10 µL AKT inhibitor IV intrathecally. Mechanical withdrawal threshold tests were performed to evaluate mechanical hypersensitivity. AKT, p-AKT, TSC2, mTOR, p-mTOR, and LC3-II protein expressions were examined by Western blot analysis.


          HBO reversed AKT/TSC2/mTOR upregulation induced by SNL and attenuated neuropathic pain. Intrathecal injection of AKT inhibitor IV decreased the activity of AKT/TSC2/mTOR pathway and increased LC3-II expression accompanied by analgesic effect in SNL rats.


          Taken together, our findings demonstrated AKT/TSC2/mTOR pathway was activated in SNL-induced neuropathic pain, and HBO treatment attenuated neuropathic pain via neutralizing AKT/TSC2/mTOR pathway activation.

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          Most cited references 42

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          An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat.

          We attempted to develop an experimental animal model for peripheral neuropathic pain. Under sodium pentobarbital anesthesia, both the L5 and L6 spinal nerves (group 1) or the L5 spinal nerve alone (group 2) of one side of the rat were tightly ligated. For comparison, a parallel study was conducted with another group of rats (group 3) which received a partial tight sciatic nerve ligation, a paradigm developed previously as a neuropathy model. Withdrawal latencies to application of radiant heat to the foot were tested for the next 16 weeks in all 3 groups. Sensitivity of the hind paw to mechanical stimulation was tested with von Frey filaments. The general behavior of each rat was noted during the entire test period. Results suggested that the surgical procedure in all 3 groups produced a long-lasting hyperalgesia to noxious heat (at least 5 weeks) and mechanical allodynia (at least 10 weeks) of the affected foot. In addition, there were behavioral signs of the presence of spontaneous pain in the affected foot. Therefore, we believe we have developed an experimental animal model for peripheral neuropathy using tight ligations of spinal nerves. The model manifests the symptoms of human patients with causalgia and is compatible with a previously developed neuropathy model. The present model has two unique features. First, the surgical procedure is stereotyped. Second, the levels of injured and intact spinal segments are completely separated, allowing independent experimental manipulations of the injured and intact spinal segments in future experiments to answer questions regarding mechanisms underlying causalgia.
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            Disruption of the beclin 1/Bcl-2 autophagy regulatory complex promotes longevity in mice

            Autophagy increases lifespan of model organisms; however, its role in promoting mammalian longevity is less well-established 1,2 . Here, we report lifespan and healthspan extension in a mouse model with increased basal autophagy. To determine the effects of constitutively increased autophagy on mammalian health, we generated targeted mutant mice with a F121A (Becn1 F121A/F121A) mutation in beclin 1 that decreases its interaction with the negative regulator, Bcl-2. We demonstrate that beclin 1/Bcl-2 interaction is disrupted in multiple tissues in Becn1 F121A/F121A knock-in (KI) mice in association with higher levels of basal autophagic flux. Compared to wild-type (WT) littermates, the lifespan of both male and female KI mice is significantly increased. The healthspan of the KI mice also improves as aging-related phenotypes are diminished, including age-related renal and cardiac pathological changes and spontaneous tumorigenesis. Moreover, mice deficient in the anti-aging protein, Klotho 3 , have increased beclin 1/Bcl-2 interaction, decreased autophagy, premature lethality and infertility which are rescued by the beclin 1 F121A mutation. Taken together, our data demonstrate that disruption of the beclin 1/Bcl-2 complex is an effective mechanism to increase autophagy, prevent premature aging, improve healthspan and promote longevity in mammals.
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              Increased miR-195 aggravates neuropathic pain by inhibiting autophagy following peripheral nerve injury.

               L Jia,  Guodong Shi,  Kun Liu (2013)
              Following peripheral nerve injury (PNI) microglia proliferates and adopts inflammation that contributes to development and maintenance of neuropathic pain. miRNAs and autophagy are two important factors in the regulation of inflammation. However, little is known about whether miRNAs regulate neuroinflammation and neuropathic pain by controlling autophagy. In the study, we demonstrated that miR-195 levels were markedly increased in rats subjected to L5 spinal nerve ligation (SNL). Upregulated miR-195 was also found in spinal microglia of rats with SNL. The overexpression of miR-195 contributed to lipopolysaccharide-induced expression of proinflammatory cytokines IL-1β, TNF-α, and iNOS in cultured microglia. Upregulated miR-195 also resulted in increased mechanical and cold hypersensitivity after PNI, whereas miR-195 inhibition reduced mechanical and cold sensitivity. We further demonstrated that PNI significantly inhibited microglial autophagy activation, whereas miR-195 inhibitor treatment increased autophagy activation and suppressed neuroinflammation in vivo and in vitro. More important, autophagy inhibition impaired miR-195 inhibitor-induced downregulation of neuroinflammation and neuropathic pain. Additionally, ATG14 was identified as the functional target of miR-195. These data demonstrated that miR-195/autophagy signaling represents a novel pathway regulating neuroinflammation and neuropathic pain, thus offering a new target for therapy of neuropathic pain. Copyright © 2013 Wiley Periodicals, Inc.

                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                23 January 2019
                : 12
                : 443-451
                [1 ]Department of Anesthesiology and Pain Management, Shengjing Hospital of China Medical University, Shenyang 110004, China, zhaop@ 123456sj-hospital.org
                [2 ]Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA 22908, USA
                Author notes
                Correspondence: Ping Zhao, Department of Anesthesiology and Pain Management, Shengjing Hospital of China Medical University, No.36 Sanhao Street, Heping District, Shenyang 110004, China, Tel +86 189 4025 8971, Email zhaop@ 123456sj-hospital.org
                © 2019 Liu 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.

                Original Research

                Anesthesiology & Pain management

                akt, hyperbaric oxygen, mtor, tsc2, neuropathic pain, autophagy


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