Upregulation of interleukin-6 on Cav3.2 T-type calcium channels in dorsal root ganglion neurons contributes to neuropathic pain in rats with spinal nerve ligation

Liu, Qingying; Chen, Wen; Fan, Xiaocen; Wang, Jiaxin; Fu, Su; Cui, Shuang; Liao, Fei-Fei; Cai, Jie; Wang, Xinhong; Huang, Yi; Su, Li; Zhong, Lijun; Yi, Ming; Liu, Fengyu; Wan, You

doi:10.1016/j.expneurol.2019.03.005

Cited by 29 publications

(42 citation statements)

References 60 publications

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“…The presence of increased plasma IL-6 levels in conjunction with increased paw thickness and synovitis supports the contribution of a systemic and local inflammatory response. Pro-inflammatory cytokines, including IL-6, are known drivers of pain responses, including neuronal activity [ 27 , 28 ] in several diseases, including RA [ 29 ]. Indeed, plasma IL-6 levels have been reported to be extremely high in pre-arthritis patients and the CIA model of RA, whereas levels of TNFα tend to decrease with the onset of disease [ 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle dysregulation in rheumatoid arthritis: Metabolic and molecular markers in a rodent model and patients

et al. 2020

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Rheumatoid arthritis (RA) is accompanied by pain, inflammation and muscle weakness. Skeletal muscle inflammation and inactivity are independently associated with muscle insulin resistance and atrophy. Our objective was to identify early molecular and biochemical markers in muscle from a rodent model of RA relative to control and subsequently identify commonality in muscle gene expression between this model and muscle from RA patients. Pain behaviour and locomotor activity were measured in a collagen-induced arthritis (CIA) model of RA (n = 9) and control (n = 9) rats. Energy substrates and metabolites, total alkaline-soluble protein:DNA ratio and mRNA abundance of 46 targeted genes were also determined in Extensor digitorum longus muscle. Expression of targeted mRNAs was quantified in Vastus Lateralis muscle from RA patients (n = 7) and healthy age-matched control volunteers (n = 6). CIA rats exhibited pain behaviour (p<0.01) and reduced activity (p<0.05) compared to controls. Muscle glycogen content was less (p<0.05) and muscle lactate content greater (p<0.01) in CIA rats. The bioinformatics analysis of muscle mRNA abundance differences from the control, predicted the activation of muscle protein metabolism and inhibition of muscle carbohydrate and fatty acid metabolism in CIA rats. Compared to age-matched control volunteers, RA patients exhibited altered muscle mRNA expression of 8 of the transcripts included as targets in the CIA model of RA. In conclusion, muscle energy metabolism and metabolic gene expression were altered in the CIA model, which was partly corroborated by targeted muscle mRNA measurements in RA patients. This research highlights the negative impact of RA on skeletal muscle metabolic homeostasis.

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Section: Discussionmentioning

confidence: 99%

Skeletal muscle dysregulation in rheumatoid arthritis: Metabolic and molecular markers in a rodent model and patients

et al. 2020

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“…The tip of the needle was then inserted through the infraorbital foramen, infraorbital canal, and foramen rotundum, and finally was positioned in the TG [27]. Different doses (10,50, and 100 ng) of VTX-2337 (5 lL) were slowly injected.…”

Section: Drugs and Administrationmentioning

confidence: 99%

“…After peripheral nerve injury, neuroinflammation occurs at different anatomical locations on the pain transmission pathway, including the TG/DRG and medulla oblongata/spinal cord, which facilitates peripheral and central sensitization [6][7][8][9]. Among inflammatory mediators, cytokines such as tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-6 are well demonstrated to be increased in the peripheral nervous system after nerve injury and enhance neuronal excitability [7,[10][11][12]. Inhibiting these cytokines using neutralizing antibodies or RNA interference inhibits the pain behavior in several neuropathic pain models [7].…”

Section: Introductionmentioning

confidence: 99%

TLR8 in the Trigeminal Ganglion Contributes to the Maintenance of Trigeminal Neuropathic Pain in Mice

et al. 2020

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Trigeminal neuropathic pain (TNP) is a significant health problem but the involved mechanism has not been completely elucidated. Toll-like receptors (TLRs) have recently been demonstrated to be expressed in the dorsal root ganglion and involved in chronic pain. Here, we show that TLR8 was persistently increased in the trigeminal ganglion (TG) neurons in model of TNP induced by partial infraorbital nerve ligation (pIONL). In addition, deletion or knockdown of Tlr8 in the TG attenuated pIONL-induced mechanical allodynia, reduced the activation of ERK and p38-MAPK, and decreased the expression of pro-inflammatory cytokines in the TG. Furthermore, intra-TG injection of the TLR8 agonist VTX-2337 induced pain hypersensitivity. VTX-2337 also increased the intracellular Ca2+ concentration, induced the activation of ERK and p38, and increased the expression of pro-inflammatory cytokines in the TG. These data indicate that TLR8 contributes to the maintenance of TNP through increasing MAPK-mediated neuroinflammation. Targeting TLR8 signaling may be effective for the treatment of TNP.

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“…Using calcium imaging, we found that TLR8 agonist VTX-2337 rapidly increased [Ca 2+ ]i in HEK293 cells transfected with TLR8 plasmid or primary cultured TG neurons. The increased [Ca 2+ ]i may due to extracellular calcium influx or intracellular calcium release from organelles, such as ER and lysosomes [7,35,[53][54][55][56]. TLR8 is localized in in the ER, endosomes, and lysosomes in human monocytes and macrophages [57,58].…”

Section: Tlr8 Is Involved In the Increase Of Intracellular Calcium Anmentioning

confidence: 99%

“…After peripheral nerve injury, neuroinflammation occurs at different anatomical locations on the pain transmission pathway, including TG/DRG and medulla oblongata/spinal cord, which facilitates peripheral sensitization and central sensitization [4][5][6]. Among the inflammatory mediators, the cytokines such as TNF-α, IL-1β, and IL-6 are well demonstrated to be increased in the peripheral nervous system after nerve injury and enhance neuronal excitability [5,[7][8][9]. Inhibiting these cytokines using neutralizing antibodies or RNA interference inhibits the neuropathic pain behavior in several neuropathic pain models [5].…”

Section: Introductionmentioning

confidence: 99%

TLR8 in the trigeminal ganglion contributes to the maintenance of trigeminal neuropathic pain

Zhao

Bai

Cao

et al. 2020

Preprint

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Background: Trigeminal neuropathic pain (TNP) is a significant health problem whereas the involved mechanism has not been completely elucidated. Toll-like receptors (TLRs) are recently demonstrated to be expressed in the dorsal root ganglion and involved in chronic pain. How TLR8 is expressed in the trigeminal ganglion (TG) after infraorbital nerve injury and whether TLR8 is involved in TNP have not been investigated. Methods: TNP model was established by the partial infraorbital nerve ligation (pIONL) in mice. The effect of TLR8 and its agonist VTX-2337 on pain hypersensitivity was checked by facial pain behavioral test. The immunostaining, real-time RT-PCR, and western blot were used to evaluate the expression of TLR8, pERK, pp38, and proinflammatory cytokines in the TG. The intracellular concentration of Ca 2+ was detected by the calcium imaging.Results: TLR8 was persistently increased in TG neurons in pIONL-induced TNP model. In addition, deletion of Tlr8 or knockdown of Tlr8 in the TG attenuated pIONL-induced mechanical allodynia, reduced the activation of ERK and p38, and decreased the expression of proinflammatory cytokines in the TG. Furthermore, intra-TG injection of TLR8 agonist VTX-2337 induced facial pain hypersensitivity. VTX-2337 also increased intracellular calcium concentration, induced activation of ERK and p38, and increased the proinflammatory cytokines expression in the TG.Conclusions: TLR8 contributes to the maintenance of TNP through increasing MAPK-mediated neuroinflammation. Targeting TLR8 signaling may be effective for the treatment of TNP. BackgroundThe sensation of nociceptive stimuli is mediated by primary sensory neurons in the dorsal root ganglion (DRG) and trigeminal ganglion (TG), which transmit noxious information to brain via spinal cord and medulla oblongata, respectively. The painful sensation of orofacial area is relayed in the TG, which gives three major branches: the ophthalmic nerve (V1), the maxillary nerve (V2), and the mandibular nerve (V3). Trigeminal neuropathic pain (TNP) is usually a result of injury or disease of one or more nerve branches (usually V2 and/or V3) of the TG and can be triggered by subtle sensory stimuli to the affected side of the face, such as light mechanical touch, brushing teeth, and chewing 4 [1]. TNP is a chronic state and difficult to treat in clinical practice. Understanding the pathophysiology of TNP is essential for the management of the pain.In recent years, increasing evidence revealed that neuroinflammation is involved in the pathological process of neuropathic pain including TNP [2, 3]. After peripheral nerve injury, neuroinflammation occurs at different anatomical locations on the pain transmission pathway, including TG/DRG and medulla oblongata/spinal cord, which facilitates peripheral sensitization and central sensitization [4][5][6]. Among the inflammatory mediators, the cytokines such as TNF-α, IL-1β, and IL-6 are well demonstrated to be increased in the peripheral nervous system after nerve injury and enhance neuronal excitability...

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Upregulation of interleukin-6 on Cav3.2 T-type calcium channels in dorsal root ganglion neurons contributes to neuropathic pain in rats with spinal nerve ligation

Cited by 29 publications

References 60 publications

Skeletal muscle dysregulation in rheumatoid arthritis: Metabolic and molecular markers in a rodent model and patients

Skeletal muscle dysregulation in rheumatoid arthritis: Metabolic and molecular markers in a rodent model and patients

TLR8 in the Trigeminal Ganglion Contributes to the Maintenance of Trigeminal Neuropathic Pain in Mice

TLR8 in the trigeminal ganglion contributes to the maintenance of trigeminal neuropathic pain

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