mTOR and Erk1/2 Signaling in the Cerebrospinal Fluid-Contacting Nucleus is Involved in Neuropathic Pain

Li, Guangling; Lu, Xianfu; Zhang, Suming; Zhou, Qinglong; Zhang, Licai

doi:10.1007/s11064-015-1564-7

Cited by 26 publications

(19 citation statements)

References 31 publications

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“…It has been recently reported that the inhibition of the Akt/mTOR pathway resulted in increased activation of ERK1/2 signaling in differentiating oligodendrocytes, but not vice versa [ 25 ]. In the present, the inhibitor of mTOR also exerted stronger effect on ERK level than that of ERK inhibitor on mTOR level in PLCγ1-transformed OA chondrocytes, indicating that the inhibition of mTOR pathway significantly increased ERK signaling; and the inhibition of the ERK pathway does not have enough impact on mTOR signaling, consistent with the very recent study in neuropathic pain [ 26 ]. Combined with the data of the existence of higher expressed the PLCγ1 and mTOR, and lower expressed ERK in human OA chondrocytes, we suggest that PLCγ1/ERK axis was blocked by the PLCγ1/mTOR axis, and the latter inhibited the effect of the PLCγ1/ERK axis on MMP-13 expression in human OA chondrocytes.…”

Section: Discussionsupporting

confidence: 90%

The Involvement of Mutual Inhibition of ERK and mTOR in PLCγ1-Mediated MMP-13 Expression in Human Osteoarthritis Chondrocytes

Liu

Cai

Zheng

et al. 2015

IJMS

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The issue of whether ERK activation determines matrix synthesis or degradation in osteoarthritis (OA) pathogenesis currently remains controversial. Our previous study shows that PLCγ1 and mTOR are involved in the matrix metabolism of OA cartilage. Investigating the interplays of PLCγ1, mTOR and ERK in matrix degradation of OA will facilitate future attempts to manipulate ERK in OA prevention and therapy. Here, cultured human normal chondrocytes and OA chondrocytes were treated with different inhibitors or transfected with expression vectors, respectively. The levels of ERK, p-ERK, PLCγ1, p-PLCγ1, mTOR, p-mTOR and MMP-13 were then evaluated by Western blotting analysis. The results manifested that the expression level of ERK in human OA chondrocytes was lower than that in human normal articular chondrocytes, and the up-regulation of ERK could promote matrix synthesis, including the decrease in MMP-13 level and the increase in Aggrecan level in human OA chondrocytes. Furthermore, the PLCγ1/ERK axis and a mutual inhibition of mTOR and ERK were observed in human OA chondrocytes. Interestingly, activated ERK had no inhibitory effect on MMP-13 expression in PLCγ1-transformed OA chondrocytes. Combined with our previous study, the non-effective state of ERK activation by PLCγ1 on MMP-13 may be partly attributed to the inhibition of the PLCγ1/mTOR axis on the PLCγ1/ERK axis. Therefore, the study indicates that the mutual inhibition of ERK and mTOR is involved in PLCγ1-mediated MMP-13 expression in human OA chondrocytes, with important implication for the understanding of OA pathogenesis as well as for its prevention and therapy.

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Section: Discussionsupporting

confidence: 90%

The Involvement of Mutual Inhibition of ERK and mTOR in PLCγ1-Mediated MMP-13 Expression in Human Osteoarthritis Chondrocytes

Liu

Cai

Zheng

et al. 2015

IJMS

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“…One study showed that mTOR signaling regulates pain-related synaptic plasticity in the entorhinal-hippocampal pathway in a model of persistent peripheral nociception induced by peripheral bee venom injections (Lyu et al, 2013). 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).…”

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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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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“…Since the supraspinal mechanism of mTOR and ERK1/2 in the persistence of neuropathic pain was reported [19]. ERK1/2, whose activation modulated noxious stimuli induced peripheral/central sensitization [20], regulated neuronal activity in neuropathic pain [21,22].…”

Section: Effects Of Dezocine On P-erk1/2 As a Results Of Neuropathic Painmentioning

confidence: 99%

“…The mTOR signaling pathway, activated in CCI-induced neuropathic pain [17,18], is involved in the transmission and modulation of pain [16,28,29]. Moreover, the blockage of mTOR signaling pathway alleviates neuropathic pain [30], and there is a supraspinal mechanism of mTOR and ERK1/2 in the development and persistence of neuropathic pain [19], with the latter regulating neuronal activity in neuropathic pain [20,21] and pain sensitization [31]. The findings exhibited that there were higher p-mTOR and p-ERK1/2 levels in CCI group than in control group, which were lowered by dezocine in dezocine+CCI group, indicating that dezocine might attenuate neuropathic pain by inactivating mTOR signaling pathway and ERK1/2 signaling pathway in rats.…”

Section: Discussionmentioning

confidence: 99%

Dezocine attenuates neuropathic pain by inhibiting ERK1/2 signaling in rats

Shen

Sheng

et al. 2019

Preprint

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Background Neuropathic pain severely impacts patients’ life quality. Dezocine can be used for the treatment of pain. The present study intended to explore the effects of dezocine in chronic constriction injury (CCI) induced neuropathic pain as well as the possible responsible molecules in rats. Methods There were 3 subgroups, ie, control group, CCI group and dezocine+CCI group. The values of paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in rats were determined by a dynamic plantar esthesiometer. The ipsilateral lumbar spinal cords in rats were extracted for the detection of protein levels of phosphorylated-mammalian target of rapamycin (p-mTOR) and p-extracellular signal-regulated kinase 1/2 (p-ERK1/2) by western blot analysis; and the mRNA and protein expression levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, and cyclooxygenase-2 (COX-2) by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Results In comparison with control group, there were lower values of PWT and PWL in CCI group, which were partially reversed by dezocine. In addition, compared to control group, the expression levels of p-mTOR, p-ERK1/2, IL-6, TNF-α and COX-2 were upregulated by CCI, which were attenuated by dezocine. Conclusions In conclusion, the analgesic effect of dezocine on CCI induced neuropathic pain might be correlated with inhibiting of the p-mTOR and p-ERK1/2 signaling pathway.

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mTOR and Erk1/2 Signaling in the Cerebrospinal Fluid-Contacting Nucleus is Involved in Neuropathic Pain

Cited by 26 publications

References 31 publications

The Involvement of Mutual Inhibition of ERK and mTOR in PLCγ1-Mediated MMP-13 Expression in Human Osteoarthritis Chondrocytes

The Involvement of Mutual Inhibition of ERK and mTOR in PLCγ1-Mediated MMP-13 Expression in Human Osteoarthritis Chondrocytes

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

Dezocine attenuates neuropathic pain by inhibiting ERK1/2 signaling in rats

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