Dysregulated TNFα promotes cytokine proteome profile increases and bilateral orofacial hypersensitivity

Zhang, Liping; Oz, Helieh S.; Mashni, M.; Westlund, Karin N.

doi:10.1016/j.neuroscience.2015.05.046

Cited by 28 publications

(20 citation statements)

References 69 publications

(84 reference statements)

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“… 15 , 52 The presence of contralateral sensory deficits have also been reported in various genetic knockout animals, included vasoactive intestinal peptide and tumor necrosis factor alpha receptor knockouts. 18 , 39 Together, these studies suggest that the causes of contralateral effects of nerve injury may stem from multiple mechanisms, and may depend on the type and severity of the injury or disease state.…”

Section: Discussionmentioning

confidence: 97%

Acute hyperalgesia and delayed dry eye after corneal abrasion injury

Hegarty

Hermes

Morgan

et al. 2018

PR9

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Introduction:Corneal nerves mediate pain from the ocular surface, lacrimation, and blinking, all of which protect corneal surface homeostasis and help preserve vision. Because pain, lacrimation and blinking are rarely assessed at the same time, it is not known whether these responses and their underlying mechanisms have similar temporal dynamics after acute corneal injury.Methods:We examined changes in corneal nerve density, evoked and spontaneous pain, and ocular homeostasis in Sprague-Dawley male rats after a superficial epithelial injury with heptanol. We also measured changes in calcitonin gene-related peptide (CGRP), which has been implicated in both pain and epithelial repair.Results:Hyperalgesia was seen 24 hours after abrasion injury, while basal tear production was normal. One week after abrasion injury, pain responses had returned to baseline levels and dry eye symptoms emerged. There was no correlation between epithelial nerve density and pain responses. Expression of both ATF3 (a nerve injury marker) and CGRP increased in trigeminal ganglia 24 hours after injury when hyperalgesia was seen, and returned to normal one week later when pain behavior was normal. These molecular changes were absent in the contralateral ganglion, despite reductions in corneal epithelial nerve density in the uninjured eye. By contrast, CGRP was upregulated in peripheral corneal endings 1 week after injury, when dry eye symptoms emerged.Conclusion:Our results demonstrate dynamic trafficking of CGRP within trigeminal sensory nerves following corneal injury, with elevations in the ganglion correlated with pain behaviors and elevations in peripheral endings correlated with dry eye symptoms.

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Section: Discussionmentioning

confidence: 97%

Acute hyperalgesia and delayed dry eye after corneal abrasion injury

Hegarty

Hermes

Morgan

et al. 2018

PR9

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“…The BDNF binds to its receptor, TrkB, on nociceptive postsynaptic neurons, inducing a shift in the chloride gradient in these cells, which in turn increases their excitability [ 99 , 100 ]. IL-1β, TNF-α and ATP are key mediators, released by activated glial cells, that sensitize neurons [ 18 , 101 ]. IL-1β facilitates N -methyl- d -aspartate receptor phosphorylation on neurons, thereby changing their synaptic strength and resulting in enhanced sensitization of neurons, which leads to behavioral hyperalgesia [ 18 , 84 , 102 ].…”

Section: Mechanisms Of Neuropathic Orofacial Pain: Glial Involvemementioning

confidence: 99%

Neuron–Glia Crosstalk and Neuropathic Pain: Involvement in the Modulation of Motor Activity in the Orofacial Region

Hossain

Unno

Ando

et al. 2017

IJMS

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Neuropathic orofacial pain (NOP) is a debilitating condition. Although the pathophysiology remains unclear, accumulating evidence suggests the involvement of multiple mechanisms in the development of neuropathic pain. Recently, glial cells have been shown to play a key pathogenetic role. Nerve injury leads to an immune response near the site of injury. Satellite glial cells are activated in the peripheral ganglia. Various neural and immune mediators, released at the central terminals of primary afferents, lead to the sensitization of postsynaptic neurons and the activation of glia. The activated glia, in turn, release pro-inflammatory factors, further sensitizing the neurons, and resulting in central sensitization. Recently, we observed the involvement of glia in the alteration of orofacial motor activity in NOP. Microglia and astroglia were activated in the trigeminal sensory and motor nuclei, in parallel with altered motor functions and a decreased pain threshold. A microglial blocker attenuated the reduction in pain threshold, reduced the number of activated microglia, and restored motor activity. We also found an involvement of the astroglial glutamate–glutamine shuttle in the trigeminal motor nucleus in the alteration of the jaw reflex. Neuron–glia crosstalk thus plays an important role in the development of pain and altered motor activity in NOP.

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“…It has been shown that TNFα mRNA and protein are significantly increased in complete Freund’s adjuvant (CFA)-treated TMJ tissues [13, 14] and trigeminal ganglia (TG) [15]. Dysregulated TNFα can promote cytokine proteome profile alteration and orofacial hypersensitivity [16]. TNFα is an inflammatory mediator produced by activated immune cells, glia, and neurons [17–19].…”

Section: Introductionmentioning

confidence: 99%

TNFα in the Trigeminal Nociceptive System Is Critical for Temporomandibular Joint Pain

et al. 2018

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Previous studies have shown that tumor necrosis factor alpha (TNFα) is significantly increased in complete Freund's adjuvant (CFA)-treated temporomandibular joint (TMJ) tissues. However, it is unclear whether TNFα in the trigeminal nociceptive system contributes to the development of TMJ pain. In the present study, we investigated the role of TNFα in trigeminal ganglia (TG) and spinal trigeminal nucleus caudalis (Sp5C) in CFA-induced inflammatory TMJ pain. Intra-TMJ injection of CFA (10 μl, 5 mg/ml) induced inflammatory pain in the trigeminal nerve V2- and V3-innervated skin areas of WT mice, which was present on day 1 after CFA and persisted for at least 10 days. TNFα in both TG and Sp5C of WT mice was upregulated after CFA injection. The CFA-induced TMJ pain was significantly inhibited in TNFα KO mice. The immunofluorescence staining showed that intra-TMJ CFA injection not only enhanced co-localization of TNFα with Iba1 (a marker for microglia) in both TG and Sp5C but also markedly increased the expression of TNFα in the Sp5C neurons. By the methylated DNA immunoprecipitation assay, we also found that DNA methylation at the TNF gene promoter region in the TG was dramatically diminished after CFA injection, indicating that epigenetic regulation may be involved in the CFA-enhanced TNFα expression in our model. Our results suggest that TNFα in the trigeminal nociceptive system plays a critical role in CFA-induced inflammatory TMJ pain.

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Dysregulated TNFα promotes cytokine proteome profile increases and bilateral orofacial hypersensitivity

Cited by 28 publications

References 69 publications

Acute hyperalgesia and delayed dry eye after corneal abrasion injury

Acute hyperalgesia and delayed dry eye after corneal abrasion injury

Neuron–Glia Crosstalk and Neuropathic Pain: Involvement in the Modulation of Motor Activity in the Orofacial Region

TNFα in the Trigeminal Nociceptive System Is Critical for Temporomandibular Joint Pain

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