Activation of mTOR in the spinal cord is required for pain hypersensitivity induced by chronic constriction injury in mice

Zhang, Wei; Sun, Xiaodong; Bo, Jin-Hua; Zhang, Juan; Liu, Xiaojie; Wu, Liu-ping; Ma, Zhengliang; Gu, Xiaoping

doi:10.1016/j.pbb.2013.07.017

Cited by 47 publications

(47 citation statements)

References 30 publications

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“…The activation of mTOR triggers phosphorylation of downstream effectors, such as P70S6K and 4EBP, to regulate mRNA translation and protein synthesis (Shih et al, 2012; Zhuang et al, 2016). Despite accumulating evidence supporting the role of mTOR signaling in pain-related memory processing (Zhang et al, 2013; Lutz et al, 2015), little is known about the molecular mechanisms of this pathway in the brain. In this study, we used behavioral, immunohistochemical, western blot and optical imaging analyses to demonstrate that mTOR signaling in the IC contributes to neuropathic pain and regulates mechanical hypersensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the levels of mTOR and extracellular signal-regulated kinase (ERK)1 and ERK2 were increased in the cerebrospinal fluid-contacting nucleus of the brainstem after nerve injury (Li et al, 2015). In the spinal cords of rats with chronic constriction injury, inhibition of mTOR with rapamycin reduces the expression of postsynaptic density protein 95 (PSD95; Zhang et al, 2013). PSD95 is enriched at excitatory synapses and mediates important interactions with receptors, such as Nmethyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (Kim et al, 2007), which are essential elements in pain hypersensitivity (Toyoda et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Mammalian Target of Rapamycin (mTOR) Signaling in the Insular Cortex Alleviates Neuropathic Pain after Peripheral Nerve Injury

Kwon

Han

Kim

et al. 2017

Front. Mol. Neurosci.

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Injury of peripheral nerves can trigger neuropathic pain, producing allodynia and hyperalgesia via peripheral and central sensitization. Recent studies have focused on the role of the insular cortex (IC) in neuropathic pain. Because the IC is thought to store pain-related memories, translational regulation in this structure may reveal novel targets for controlling chronic pain. Signaling via mammalian target of rapamycin (mTOR), which is known to control mRNA translation and influence synaptic plasticity, has been studied at the spinal level in neuropathic pain, but its role in the IC under these conditions remains elusive. Therefore, this study was conducted to determine the role of mTOR signaling in neuropathic pain and to assess the potential therapeutic effects of rapamycin, an inhibitor of mTORC1, in the IC of rats with neuropathic pain. Mechanical allodynia was assessed in adult male Sprague-Dawley rats after neuropathic surgery and following microinjections of rapamycin into the IC on postoperative days (PODs) 3 and 7. Optical recording was conducted to observe the neural responses of the IC to peripheral stimulation. Rapamycin reduced mechanical allodynia and downregulated the expression of postsynaptic density protein 95 (PSD95), decreased neural excitability in the IC, thereby inhibiting neuropathic pain-induced synaptic plasticity. These findings suggest that mTOR signaling in the IC may be a critical molecular mechanism modulating neuropathic pain.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of Mammalian Target of Rapamycin (mTOR) Signaling in the Insular Cortex Alleviates Neuropathic Pain after Peripheral Nerve Injury

Kwon

Han

Kim

et al. 2017

Front. Mol. Neurosci.

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“…Activation of spinal mTOR is required for neuropathy-induced pain hypersensitivity [42]; and phosphorylation of Ser-2448 of mTOR is a biomarker for the activation status of mTOR [70]. Inhibition of the spinal mTOR pathway attenuates mechanical hyperalgesia in neuropathic rats [39,40].…”

Section: Discussionmentioning

confidence: 99%

“…administration of an mTOR inhibitor, rapamycin, or TGF-beta, attenuates nociception in cases of neuropathic pain [39e41]. Zhang et al [42] and Chen et al [41] also reported up-regulation of phosphorylated mTOR (phospho-mTOR) and down-regulation of TGF-b1 in neuropathic rats. However, the antinociceptive effects of PCD-1 on spinal glia, mTOR, and TGF-beta in the context of neuropathy are unclear.…”

Section: Introductionmentioning

confidence: 99%

The use of the antimicrobial peptide piscidin (PCD)-1 as a novel anti-nociceptive agent

Chen¹,

Huang²,

Liao³

et al. 2015

Biomaterials

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“…Zhang W et al reported that intrathecal injection of rapamycin could reduce neuropathic pain by inhibiting mTOR [35]. Tateda S et al demonstrated that rapamycin, as an inhibitor of mTOR, suppressed the development of neuropathic pain when the spinal cord was injured [36].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-183 Suppresses Neuropathic Pain and Expression of AMPA Receptors by Targeting mTOR/VEGF Signaling Pathway

Xie

et al. 2017

Cell Physiol Biochem

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Background: Neuropathic pain is a type of chronic pain that results from dysfunctions of the somatosensory nerve system. This study was aimed to investigate the effect of mTOR/VEGF signaling pathway on neuropathic pain and the regulation mechanisms of miR-183 on AMPA Receptors through mTOR/VEGF signaling pathway. Methods: Chronic compress injury (CCI) model was constructed in the current study, we used paw withdrawal mechanic threshold (PWMT) and paw withdrawal thermal latency (PWTL) to observe mTOR and VEGF receptors. Dual luciferase analysis, western blot and qRT-PCR were also applied to complete this experiment. Results: It was observed that the inhibition of mTOR and VEGF receptors could significantly relieve neuropathic pain in the CCI model. Moreover mTOR was confirmed as the direct target of miR-183. Furthermore, miR-183 could modulate VEGF through regulating mTOR expressions. We also found the expressions of AMPA receptors (i.e. GluR1 and GluR2), located in the downstream of mTOR/VEGF signaling pathway, were significantly upregulated when miR-183 was downregulated or when the mTOR/VEGF signaling pathway was activated. Conclusion: The inhibition of mTOR or VEGF receptors can significantly relieve neuropathic pain, and the upregulation of miR-183 can suppress AMPA receptors by inhibiting mTOR/VEGF pathway.

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Activation of mTOR in the spinal cord is required for pain hypersensitivity induced by chronic constriction injury in mice

Cited by 47 publications

References 30 publications

Inhibition of Mammalian Target of Rapamycin (mTOR) Signaling in the Insular Cortex Alleviates Neuropathic Pain after Peripheral Nerve Injury

Inhibition of Mammalian Target of Rapamycin (mTOR) Signaling in the Insular Cortex Alleviates Neuropathic Pain after Peripheral Nerve Injury

The use of the antimicrobial peptide piscidin (PCD)-1 as a novel anti-nociceptive agent

MicroRNA-183 Suppresses Neuropathic Pain and Expression of AMPA Receptors by Targeting mTOR/VEGF Signaling Pathway

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