IL-6 induced upregulation of T-type Ca<sup>2+</sup> currents and sensitization of DRG nociceptors is attenuated by MNK inhibition

Jeevakumar, Vivek; Sardar, Aysha Khalid Al; Farah, Mohamed; Smithhart, Clay Matthew; Price, Theodore J.; Dussor, Gregory

doi:10.1152/jn.00188.2020

Cited by 30 publications

(26 citation statements)

References 57 publications

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“…A study demonstrated that MKNK2 is involved in mechanisms of nociceptor plasticity and chronic pain development (Moy et al., 2017 ). And MKNK inhibition was shown to reduce sensitization of dorsal root ganglion nociceptors (Jeevakumar et al., 2020 ). The kinase MKNK2 was found by its interaction with the mitogen‐activated protein kinases (MAPKs), p38‐MAPK, and extracellular signal‐regulated kinase (ERK) (Waskiewicz et al., 1997 ).…”

Section: Discussionmentioning

confidence: 99%

MiR‐223‐3p alleviates trigeminal neuropathic pain in the male mouse by targeting MKNK2 and MAPK/ERK signaling

et al. 2022

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Background: Trigeminal neuralgia (TN) is a neuropathic pain that occurs in branches of the trigeminal nerve. MicroRNAs (miRNAs) have been considered key mediators of neuropathic pain. This study was aimed to elucidate the pathophysiological function and mechanisms of miR-223-3p in mouse models of TN. Methods: Infraorbital nerve chronic constriction injury (CCI-ION) was applied in male C57BL/6J mice to establish mouse models of TN. Pain responses were assessed utilizing Von Frey method. The expression of miR-223-3p, MKNK2, and MAPK/ERK pathway protein in trigeminal ganglions (TGs) of CCI-ION mice was measured using RT-qPCR and Western blotting. The concentrations of inflammatory cytokines were evaluated using Western blotting. The relationship between miR-223-3p and MKNK2 was tested by a luciferase reporter assay. Results: We found that miR-223-3p was downregulated, while MKNK2 was upregulated in TGs of CCI-ION mice. MiR-223-3p overexpression by an intracerebroventricular injection of Lv-miR-223-3p attenuated trigeminal neuropathic pain in CCI-ION mice, as well as reduced the protein levels of pro-inflammatory cytokines in TGs of CCI-ION mice. MKNK2 was verified to be targeted by miR-223-3p. Additionally, miR-223-3p overexpression decreased the phosphorylation levels of ERK1/2, JNK, and p38 protein in TGs of CCI-ION mice to inhibit MAPK/ERK signaling. Conclusions: Overall, miR-223-3p attenuates the development of TN by targeting MKNK2 to suppress MAPK/ERK signaling.

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Section: Discussionmentioning

confidence: 99%

MiR‐223‐3p alleviates trigeminal neuropathic pain in the male mouse by targeting MKNK2 and MAPK/ERK signaling

et al. 2022

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“…As mentioned above, IL-1b, IL-6, PGE 2 , TNFa and CCL2 released by macrophages can stimulate specific cognate receptors on nociceptive neurons contributing to the development of neuropathic pain. 213,[251][252][253][254] Activated macrophages secrete HMGB1, which binds to TLR4 receptors on sensory neurons to play a role in the pathogenesis of neuropathic pain in animal models. 46,239,240 Hydrogen sulfide (H 2 S) is generated in activated macrophages and contributes to neuronal hyperexcitation by upregulating and activating neuronal calcium channels (transient receptor potential cation channel A1; TRPA1).…”

Section: Macrophage To Sensory Neuron Interactionsmentioning

confidence: 99%

The Role of Neuro-Immune Interactions in Chronic Pain: Implications for Clinical Practice

Su¹,

Zhang²,

He³

et al. 2022

JPR

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Chronic pain remains a public health problem and contributes to the ongoing opioid epidemic. Current pain management therapies still leave many patients with poorly controlled pain, thus new or improved treatments are desperately needed. One major challenge in pain research is the translation of preclinical findings into effective clinical practice. The local neuroimmune interface plays an important role in the initiation and maintenance of chronic pain and is therefore a promising target for novel therapeutic development. Neurons interface with immune and immunocompetent cells in many distinct microenvironments along the nociceptive circuitry. The local neuroimmune interface can modulate the activity and property of the neurons to affect peripheral and central sensitization. In this review, we highlight a specific subset of many neuroimmune interfaces. In the central nervous system, we examine the interface between neurons and microglia, astrocytes, and T lymphocytes. In the periphery, we profile the interface between neurons in the dorsal root ganglion with T lymphocytes, satellite glial cells, and macrophages. To bridge the gap between preclinical research and clinical practice, we review the preclinical studies of each neuroimmune interface, discuss current clinical treatments in pain medicine that may exert its action at the neuroimmune interface, and highlight opportunities for future clinical research efforts.

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“…Inhibition of MNKs with cercosporamide or genetic elimination of eIF4E phosphorylation attenuates mechanical hypersensitivity evoked by IL‐6 (Moy et al, 2017). Similarly, a blockade of MNKs with eFT‐508 interferes with the sensitization of nociceptors by IL‐6 (Jeevakumar et al, 2020). A second inflammatory mediator, nerve growth factor (NGF), stimulates mTOR and increases nascent protein synthesis (Melemedjian et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Inhibition of MNKs with cercosporamide or genetic elimination of eIF4E phosphorylation attenuates mechanical hypersensitivity evoked by IL-6 (Moy et al, 2017). Similarly, a blockade of MNKs with eFT-508 interferes with the sensitization of nociceptors by IL-6 (Jeevakumar et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

A role for translational regulation by S6 kinase and a downstream target in inflammatory pain

Peña

Kunder

Lou

et al. 2021

British J Pharmacology

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Background and Purpose Translational controls pervade neurobiology. Nociceptors play an integral role in the detection and propagation of pain signals. Nociceptors can undergo persistent changes in their intrinsic excitability. Pharmacological disruption of nascent protein synthesis diminishes acute and chronic forms of pain‐associated behaviours. However, the targets of translational controls that facilitate plasticity in nociceptors are unclear. Experimental Approach We used ribosome profiling to probe the translational landscape in dorsal root ganglion (DRG) neurons from male Swiss‐Webster mice, after treatment with nerve growth factor and IL‐6. Expression dynamics of c‐Fos were followed with immunoblotting and immunohistochemistry. The involvement of ribosomal protein S6 kinase 1 (S6K1), a downstream component of mTOR signalling, in the control of c‐Fos levels was assessed with low MW inhibitors of S6K1 (DG2) or c‐Fos (T‐5224), studying their effects on nociceptor activity in vitro using multielectrode arrays (MEAs) and pain behaviour in vivo in Swiss‐Webster mice using the hyperalgesic priming model. Key Results c‐Fos was expressed in sensory neurons. Inflammatory mediators that promote pain in both humans and rodents promote c‐Fos translation. The mTOR effector S6K1 is essential for c‐Fos biosynthesis. Inhibition of S6K1 or c‐Fos with low MW compounds diminished mechanical and thermal hypersensitivity in response to inflammatory cues. Additionally, both inhibitors reduced evoked nociceptor activity. Conclusion and implications Our data show a novel role of S6K1 in modulating the rapid response to inflammatory mediators, with c‐Fos being one key downstream target. Targeting the S6 kinase pathway or c‐Fos is an exciting new avenue for pain‐modulating compounds.

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IL-6 induced upregulation of T-type Ca²⁺ currents and sensitization of DRG nociceptors is attenuated by MNK inhibition

Cited by 30 publications

References 57 publications

MiR‐223‐3p alleviates trigeminal neuropathic pain in the male mouse by targeting MKNK2 and MAPK/ERK signaling

MiR‐223‐3p alleviates trigeminal neuropathic pain in the male mouse by targeting MKNK2 and MAPK/ERK signaling

The Role of Neuro-Immune Interactions in Chronic Pain: Implications for Clinical Practice

A role for translational regulation by S6 kinase and a downstream target in inflammatory pain

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IL-6 induced upregulation of T-type Ca2+ currents and sensitization of DRG nociceptors is attenuated by MNK inhibition

Cited by 30 publications

References 57 publications

MiR‐223‐3p alleviates trigeminal neuropathic pain in the male mouse by targeting MKNK2 and MAPK/ERK signaling

MiR‐223‐3p alleviates trigeminal neuropathic pain in the male mouse by targeting MKNK2 and MAPK/ERK signaling

The Role of Neuro-Immune Interactions in Chronic Pain: Implications for Clinical Practice

A role for translational regulation by S6 kinase and a downstream target in inflammatory pain

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IL-6 induced upregulation of T-type Ca²⁺ currents and sensitization of DRG nociceptors is attenuated by MNK inhibition