TNF-α enhances the currents of voltage gated sodium channels in uninjured dorsal root ganglion neurons following motor nerve injury

Chen, Xi; Pang, Rui‐Ping; Shen, Kai-Feng; Zimmermann, M.; Xin, Wenjun; Li, Yongyong; Liu, Xianguo

doi:10.1016/j.expneurol.2010.11.017

Cited by 87 publications

(69 citation statements)

References 58 publications

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“…72,75 These also promote the activation of DRG glial satellite cells, and together they may be responsible for the sensitization and ectopic activity seen in DRG neurons. 76 It is thought that this may contribute to the neuropathic pain seen in this ventral root transection model. However, this study found that there were no phenotypic changes in the peptidergic, non-peptidergic, and neurofilament-rich subpopulations of neurons, and is consistent with the spared-nerve injury model of neuropathic pain.…”

Section: Discussionmentioning

confidence: 94%

Segmental Spinal Root Avulsion in the Adult Rat: A Model To Study Avulsion Injury Pain

Chew

Murrell

Carlstedt

et al. 2013

Journal of Neurotrauma

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Road traffic accidents are the most common cause of avulsion injury, in which spinal roots are torn from the spinal cord. Patients suffer from a loss of sensorimotor function, intractable spontaneous pain, and border-zone hypersensitivity. The neuropathic pains are particularly difficult to treat because the lack of a well-established animal model of avulsion injury prevents identifying the underlying mechanisms and hinders the development of efficacious drugs. This article describes a hindlimb model of avulsion injury in adult rats where the L5 dorsal and ventral spinal root are unilaterally avulsed (spinal root avulsion [SRA]), leaving the adjacent L4 spinal root intact. SRA produced a significant ipsilateral hypersensitivity to mechanical and thermal stimulation by 5 days compared with sham-operated or naïve rats. This hypersensitivity is maintained for up to 60 days. No autotomy was observed and locomotor deficits were minimal. The hypersensitivity to peripheral stimuli could be temporarily ameliorated by administration of amitriptyline and carbamazepine, drugs that are currently prescribed to avulsion patients. Histological assessment of the L4 ganglion cells revealed no significant alterations in calcitonin gene-related peptide (CGRP), IB4, transient receptor potential cation channel subfamily V member 1 (TrpV1), or N52 staining across groups. Immunohistochemistry of the spinal cord revealed a localized glial response, phagocyte infiltration, and neuronal loss within the ipsilateral avulsed segment. A comparable response from glia and phagocytes was also found in the intact L4 spinal cord, supporting the role for central mechanisms within the L4-5 spinal cord in contributing to the generation of the pain-related behavior. The SRA model provides a platform to investigate possible new pharmacological treatments for avulsion injuries.

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Section: Discussionmentioning

confidence: 94%

Segmental Spinal Root Avulsion in the Adult Rat: A Model To Study Avulsion Injury Pain

Chew

Murrell

Carlstedt

et al. 2013

Journal of Neurotrauma

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“…TNFα directly enhances neuronal excitability [11] and increases trafficking of Ca 2+ -permeable AMPA receptors (CP-AMPARs) to the plasma membrane, an effect that can ultimately lead to cell death [29,92]. CP-AMPARs and intracellular calcium are also implicated in a variety of processes associated with spinal nociception [33,35,52].…”

Section: Discussionmentioning

confidence: 99%

Peripheral noxious stimulation reduces withdrawal threshold to mechanical stimuli after spinal cord injury: Role of tumor necrosis factor alpha and apoptosis

Garraway

Woller

Huie

et al. 2014

Pain

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We previously showed that peripheral noxious input after spinal cord injury (SCI) inhibits beneficial spinal plasticity and impairs recovery of locomotor and bladder functions. These observations suggest that noxious input may similarly affect the development and maintenance of chronic neuropathic pain, an important consequence of SCI. In adult rats with a moderate contusion SCI, we investigated the effect of noxious tail stimulation, administered one day after SCI, on mechanical withdrawal responses to von Frey stimuli from 1 to 28 days, post-treatment. In addition, because the pro-inflammatory cytokine tumor necrosis factor α (TNFα) is implicated in numerous injury-induced processes including pain hypersensitivity, we assessed the temporal and spatial expression of TNFα, TNF receptors, and several downstream signaling targets after stimulation. Our results showed that unlike sham surgery or SCI only, nociceptive stimulation following SCI induced mechanical sensitivity by 24 hours. These behavioral changes were accompanied by increased expression of TNFα. Cellular assessments of downstream targets of TNFα revealed that nociceptive stimulation increased the expression of caspase 8 and the active subunit (12 kDa) of caspase 3 at a time point consistent with the onset of mechanical allodynia, indicative of active apoptosis. In addition, immunohistochemical analysis revealed distinct morphological signs of apoptosis in neurons and microglia at 24 hours post-stimulation. Interestingly, expression of the inflammatory mediator NFκB was unaltered by nociceptive stimulation. These results suggest that noxious input caudal to the level of SCI can increase the onset and expression of behavioral responses indicative of pain, potentially involving TNFα signaling.

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“…Although IL-6 is critically involved in the cascade of events after nerve injury leading to the development and maintenance of pain behaviors (DeLeo et al, 1996;Dubovy et al, 2013;Vissers et al, 2005;Wei et al, 2013a), the peripheral mechanism by which IL-6 elicits nociception is still largely unknown. Our previous work has shown that TNF-a through triggering the abnormal Na + channels expression increases the excitability of primary afferents after L5-VRT (Chen et al, 2011), which contributes to neuropathic pain by sequentially leading to the central sensitization. Maybe IL-6 possesses a similar mechanism in regulating the sensitivity of primary sensory neurons.…”

Section: Calpain-2 Triggers Il-6 Up-regulation In Drg Neuronsmentioning

confidence: 99%

Calpain-2 contributes to neuropathic pain following motor nerve injury via up-regulating interleukin-6 in DRG neurons

Zang

Chen

Liao

et al. 2015

Brain, Behavior, and Immunity

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TNF-α enhances the currents of voltage gated sodium channels in uninjured dorsal root ganglion neurons following motor nerve injury

Cited by 87 publications

References 58 publications

Segmental Spinal Root Avulsion in the Adult Rat: A Model To Study Avulsion Injury Pain

Segmental Spinal Root Avulsion in the Adult Rat: A Model To Study Avulsion Injury Pain

Peripheral noxious stimulation reduces withdrawal threshold to mechanical stimuli after spinal cord injury: Role of tumor necrosis factor alpha and apoptosis

Calpain-2 contributes to neuropathic pain following motor nerve injury via up-regulating interleukin-6 in DRG neurons

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