Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats

Xiao, Xing; Zhao, Xiaozheng; Xu, Lingchi; Yue, Lupeng; Liu, Fengyu; Cai, Jie; Liao, Fei-Fei; Kong, Jinge; Xing, Guo-Gang; Yi, Ming; Wan, You

doi:10.1097/01.j.pain.0000460351.30707.c4

Cited by 41 publications

(27 citation statements)

References 32 publications

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“…H + can be generated by activating the outer peripheral nociceptors, which have an important role in inflammatory pain. During inflammatory pain conduction, noxious stimulation signals are transmitted by the primary sensory neurons in trigeminal ganglia (TG) and dorsal root ganglion to the dorsal horn of the lumbar spinal cord by synaptic transmission (15,16).…”

Section: Introductionmentioning

confidence: 99%

Bupivacaine effectively relieves inflammation-induced pain by suppressing activation of the NF-κB signalling pathway and inhibiting the activation of spinal microglia and astrocytes

Zhang

Deng

2017

Experimental and Therapeutic Medicine

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Abstract. The pain induced by local acute inflammation results in mild to severe discomfort, in addition to the possibility of physiological dysfunction and psychiatric disorders, such as sleep disorders and depression. However, the pathogenesis of pain is yet to be fully elucidated. In the present study, the effects of bupivacaine were explored in rat models inflammatory pain in order to investigate the anti-pain mechanism of bupivacaine. Complete Freund's adjuvant (CFA) was injected into the right rear foot of the rats to establish a model of transient inflammation-induced pain. Rats were randomly divided into four groups (n=8): CFA, CFA plus bupivacaine, CFA plus saline and untreated. The mechanical withdrawal threshold (MWT) of the rats was detected prior to and following CFA injection, and the results demonstrated that the MWT in the right rear foot significantly decreased from the 1st day of CFA injection (P<0.01; n=8), as compared with the untreated controls. Bupivacaine treatment was demonstrated to significantly increase the MWT of rats treated with CFA stimulation, as compared with the CFA group (P<0.01). Rotarod testing was performed to assess the motor activity of the rats, and the results demonstrated no significant differences among the four groups (P>0.05). Furthermore, the respective body weights of the rats were determined every two days before and after CFA injection, and no significant differences were detected among the four groups (P>0.05). Western blot analysis was performed to analyze expression levels of IκB and nuclear factor (NF)-κB, and the results demonstrated that bupivacaine increased the expression of IκB and decreased the expression levels of NF-κB, as compared with the rats with CFA-induced inflammatory responses, suggesting that bupivacaine inhibited NF-κB activation in the dorsal horn of the lumbar spinal cord of the model rats. Furthermore, reverse transcription-quantitative polymerase chain reaction analysis was performed to analyze the expression levels of inflammatory cytokines, which demonstrated that bupivacaine significantly inhibited the expression of TNF-α, IL-1β and IL-6, as compared with the untreated group (P<0.01). Moreover, bupivacaine treatment significantly decreased the expression of spinal microglial marker OX42 and astrocyte marker-glial fibrillary acidic protein, as compared with the rats in the CFA group (P<0.01). The present findings demonstrated that treatment with bupivacaine significantly decreased the activation of microglia and astrocytes in rat models of inflammatory pain. Therefore, the present results may provide clarification of the pathogenesis and mechanism of inflammation-induced pain and may provide novel therapeutic strategies for the clinical treatment of pain.

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Section: Introductionmentioning

confidence: 99%

Bupivacaine effectively relieves inflammation-induced pain by suppressing activation of the NF-κB signalling pathway and inhibiting the activation of spinal microglia and astrocytes

Zhang

Deng

2017

Experimental and Therapeutic Medicine

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“…Transient receptor potential vanilloid receptor 1 (TRPV1) plays an important role in both itch transduction and pain, specifically heat pain. The TRPV1 channel is activated by temperatures in the noxious range (> 42 °C) .…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the histaminergic itch provocation itself establishes neurogenic inflammation in the area, which has been shown not to differ when heat pain is applied. 21 Transient receptor potential vanilloid receptor 1 (TRPV1) plays an important role in both itch transduction [22][23][24][25][26] and pain, [27][28][29][30][31][32][33] specifically heat pain. The TRPV1 channel is activated by temperatures in the noxious range (> 42°C).…”

Section: Discussionmentioning

confidence: 99%

Antipruritic effects of transient heat stimulation on histaminergic and nonhistaminergic itch

2019

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Summary Background Chronic itch is notoriously difficult to treat. Counterstimuli are able to inhibit itch, but this principle is difficult to apply in clinical practice, and the mechanisms behind counterstimulation‐induced itch suppression in humans are unclear. Objectives Firstly, to analyse the stimulus–response effects of transient heat stimuli on histaminergic and nonhistaminergic itch, and secondly, to investigate whether the antipruritic effect depends on homotopic (peripheral mediation) or heterotopic (central mediation) counterstimulation relative to the itch provocation site. Methods Eighteen healthy volunteers participated (eight female, mean age 25·7 ± 0·8 years). Itch was evoked on premarked areas of the volar forearms, by either histamine (1% solution) or cowhage (35–40 spicules). In addition to the itch provocations (experiment 1), 5‐s homotopic heat stimuli at 32, 40, 45 or 50 °C were applied. In experiment 2, heat stimuli were applied either homotopically, intrasegmentally (next to the provocation site) or extrasegmentally (dorsal forearm). Itch intensity was evaluated throughout the procedures using a digital visual analogue scale. Results Homotopic counterstimuli inhibited histaminergic itch by 41·3% at 45 °C (P < 0·01) and by 76·7% at 50 °C (P < 0·001). Cowhage‐induced itch was less prone to counterstimulation and was significantly diminished only at 50 °C, by 43·6% (P = 0·009). Counterstimulations applied heterotopically were not able to inhibit itch significantly. Conclusions Itch pathway‐specific effects of counterstimuli were observed between homo‐ and heterotopic stimulation. Histaminergic itch was robustly inhibited by short‐term homotopic noxious heat stimuli for up to 10 min. Nonhistaminergic itch was only weakly inhibited. The inhibitory effects exerted by the short‐term heat stimuli only occurred following homotopic counterstimulation.

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“…Thus, it was shown that Src‐mediated phosphorylation of TRPV1 at Tyr200 leads to modulation of subcellular trafficking of TRPV1 to the plasma membrane (X. Zhang, Huang, & McNaughton, ). On the other hand protein tyrosine phosphatase (PTP) Shp‐1 dephosporylates TRPV1 in dorsal root ganglion (DRG) neurons and reduces the inflammatory pain in rats, induced by Complete Freund's adjuvant (Xiao et al, ). Similarly, TRPV4 phosphorylation by Src family kinases, in different cell lines has been reported.…”

Section: Introductionmentioning

confidence: 99%

Regulation of TRPM8 channel activity by Src‐mediated tyrosine phosphorylation

Manolache

Şelescu

Maier

et al. 2019

Journal Cellular Physiology

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The transient receptor potential melastatin type 8 (TRPM8) receptor channel is expressed in primary afferent neurons where it is the main transducer of innocuous cold temperatures and also in a variety of tumors, where it is involved in progression and metastasis. Modulation of this channel by intracellular signaling pathways has therefore important clinical implications. We investigated the modulation of recombinant and natively expressed TRPM8 by the Src kinase, which is known to be involved in cancer pathophysiology and inflammation. Human TRPM8 expressed in HEK293T cells is constitutively tyrosine phosphorylated by Src which is expressed either heterologously or endogenously. Src action on TRPM8 potentiates its activity, as treatment with PP2, a selective Src kinase inhibitor, reduces both TRPM8 tyrosine phosphorylation and cold‐induced channel activation. RNA interference directed against the Src kinase diminished the extent of PP2‐induced functional downregulation of TRPM8, confirming that PP2 acts mainly through Src inhibition. Finally, the effect of PP2 on TRPM8 cold activation was reproduced in cultured rat dorsal root ganglion neurons, and this action was antagonized by the protein tyrosine phosphatase inhibitor pervanadate, confirming that TRPM8 activity is sensitive to the cellular balance between tyrosine kinases and phosphatases. This positive modulation of TRPM8 by Src kinase may be relevant for inflammatory pain and cancer signaling.

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Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats

Cited by 41 publications

References 32 publications

Bupivacaine effectively relieves inflammation-induced pain by suppressing activation of the NF-κB signalling pathway and inhibiting the activation of spinal microglia and astrocytes

Bupivacaine effectively relieves inflammation-induced pain by suppressing activation of the NF-κB signalling pathway and inhibiting the activation of spinal microglia and astrocytes

Antipruritic effects of transient heat stimulation on histaminergic and nonhistaminergic itch

Regulation of TRPM8 channel activity by Src‐mediated tyrosine phosphorylation

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