Interleukin-6-mediated functional upregulation of TRPV1 receptors in dorsal root ganglion neurons through the activation of JAK/PI3K signaling pathway

Fang, Dong; Kong, Lingyu; Cai, Jie; Li, Song; Liu, Xiaodan; Han, Ji-Sheng; Xing, Guo-Gang

doi:10.1097/j.pain.0000000000000158

Cited by 146 publications

(105 citation statements)

References 82 publications

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“…We next investigated whether IL-6 by itself directly activates DRG sensory neurons, as suggested in other studies (Dubovy et al, 2013; Fang et al, 2015; Leskovar et al, 2000; Wei et al, 2013). Surprisingly, IL-6 did not induce obvious [Ca 2+ ] i responses, unlike capsaicin in the same neurons (Figure S1A).…”

Section: Resultsmentioning

confidence: 84%

Sustained Elevated Adenosine via ADORA2B Promotes Chronic Pain through Neuro-immune Interaction

Adebiyi

Luo

et al. 2016

Cell Reports

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The molecular mechanisms of chronic pain are poorly understood and effective mechanism-based treatments are lacking. Here we report that mice lacking adenosine deaminase (ADA), an enzyme necessary for the breakdown of adenosine, displayed unexpected chronic mechanical and thermal hypersensitivity due to sustained elevated circulating adenosine. Extending from Ada−/− mice, we further discovered that prolonged elevated adenosine contributed to chronic pain behaviors in two additional independent animal models:1) sickle cell disease mice, a model of severe pain with limited treatment, and 2) complete Freund’s adjuvant paw-injected mice, a well-accepted inflammatory model of chronic pain. Mechanistically, we revealed that activation of adenosine A2B receptors on myeloid cells caused nociceptor hyperexcitability and promoted chronic pain via soluble IL-6 receptor trans-signaling, our findings determined that prolonged accumulated circulating adenosine contributes to chronic pain by promoting immune-neuronal interaction and revealed multiple therapeutic targets.

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Section: Resultsmentioning

confidence: 84%

Sustained Elevated Adenosine via ADORA2B Promotes Chronic Pain through Neuro-immune Interaction

Adebiyi

Luo

et al. 2016

Cell Reports

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“…The Ca 2+ -permeable mechanisms 28, 29 such as certain TRP channels 30, 31 might be involved in CXCL12-induced hyperexcitability in DRG neurons. Suppression of functional upregulation of TRPV1 in DRG neurons could reduce hyperexcitability of DRG neurons and pain hypersensitity in bone cancer rats 32 . In our study the co-expression of CXCR4 with TRPV1 supported a possible association of TRPV1 with neuronal hyperexcitability.…”

Section: Discussionmentioning

confidence: 98%

Effect of CXCL12/CXCR4 signaling on neuropathic pain after chronic compression of dorsal root ganglion

Huang

et al. 2017

Sci Rep

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Neuropathic pain is a complex, chronic pain state that often accompanies tissue damage, inflammation or injury of the nervous system. However the underlying molecular mechanisms still remain unclear. Here, we showed that CXCL12 and CXCR4 were upregulated in the dorsal root ganglion (DRG) after chronic compression of DRG (CCD), and some CXCR4 immunopositive neurons were also immunopositive for the nociceptive neuronal markers IB4, TRPV1, CGRP, and substance P. The incidence and amplitude of CXCL12-induced Ca2+ response in primary sensory neurons from CCD mice was significantly increased compared to those from control animals. CXCL12 depolarized the resting membrane potential, decreased the rheobase, and increased the number of action potentials evoked by a depolarizing current at 2X rheobase in neurons from CCD mice. The mechanical and thermal hypernociception after CCD was attenuated by administration of a CXCR4 antagonist AMD3100. These findings suggest that CXCL12/CXCR4 signaling contributes to hypernociception after CCD, and targeting CXCL12/CXCR4 signaling pathway may alleviate neuropathic pain.

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“…IL-1β also activates IL-1R1 on nociceptor neurons to increase TRPV1 expression and, consequently, pain sensitivity to thermal stimuli [29]. IL-6 also contributes to inflammatory pain by inducing prostaglandin production [30] and by binding to its signal transducer gp130 expressed by nociceptors, leading to increased TRPV1 and TRPA1 expression [31,32]. TNFα-induced neuronal sensitization and hyperalgesia is dependent on TRPV1 and TRPA1 [33,34].…”

Section: Modulation Of Pain Sensitivity By Immune Cellsmentioning

confidence: 99%

Nociceptor Sensory Neuron–Immune Interactions in Pain and Inflammation

Pinho‐Ribeiro

Verri

Chiu

2017

Trends in Immunology

659

556

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Nociceptor sensory neurons protect organisms from dangers by eliciting pain and driving avoidance. Pain also accompanies many types of inflammation and injury. It is increasingly clear that active crosstalk occurs between nociceptor neurons and the immune system to regulate pain, host defense, and inflammatory diseases. Immune cells at peripheral nerve terminals and within the spinal cord release mediators that modulate mechanical and thermal sensitivity. In turn, nociceptor neurons release neuropeptides and neurotransmitters from nerve terminals that regulate vascular, innate, and adaptive immune cell responses. Therefore, the dialogue between nociceptor neurons and the immune system is a fundamental aspect of inflammation, both acute and chronic. A better understanding of these interactions could produce approaches to treat chronic pain and inflammatory diseases.

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Interleukin-6-mediated functional upregulation of TRPV1 receptors in dorsal root ganglion neurons through the activation of JAK/PI3K signaling pathway

Cited by 146 publications

References 82 publications

Sustained Elevated Adenosine via ADORA2B Promotes Chronic Pain through Neuro-immune Interaction

Sustained Elevated Adenosine via ADORA2B Promotes Chronic Pain through Neuro-immune Interaction

Effect of CXCL12/CXCR4 signaling on neuropathic pain after chronic compression of dorsal root ganglion

Nociceptor Sensory Neuron–Immune Interactions in Pain and Inflammation

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