Lipopolysaccharide-Induced Upregulation of Tumor Necrosis Factor-α (TNF-α) and TNF Receptors in Rat Sciatic Nerve

Wang, Youhua; Zhou, Dan; Shen, Qin; Cheng, Chun; Liu, Haiou; Qin, Yongwei; Sun, Linlin; Xiao, Feng; Zhao, Jian; Shen, Aiguo

doi:10.1007/s12031-007-0036-1

Cited by 10 publications

(2 citation statements)

References 35 publications

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“…While it is possible that technical limitations hampered our ability to detect TNFR1 in dural nerve fibers, the immunolabeling of vascular TNFR1 suggests otherwise. The lack of axonal TNFR1 expression in our study is in agreement with previous studies showing its lack of axonal expression in the skin [16] and sciatic nerve [41,42]. Although we do not discount the possibility that a very limited distal axonal transport of trigeminal TNFR1 hinders its immunohistochemical detection, it is tempting to speculate that TNFR1 expression in nociceptive neurons is purely somatic.…”

Section: Discussionsupporting

confidence: 89%

Tumor necrosis factor-α induces sensitization of meningeal nociceptors mediated via local COX and p38 MAP kinase actions

Zhang

Kainz

Burstein

et al. 2011

Pain

127

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The proinflammatory cytokine TNF-alpha has been shown to promote activation and sensitization of primary afferent nociceptors. The downstream signaling processes that play a role in promoting this neuronal response remain however controversial. Increased TNF-alpha plasma levels during migraine attacks suggest that local interaction between this cytokine and intracranial meningeal nociceptors plays a role in promoting the headache. Here, using in vivo single unit recording in the trigeminal ganglia of anesthetized rats, we show that meningeal TNF-alpha action promotes a delayed mechanical sensitization of meningeal nociceptors. Using immunohistochemistry, we provide evidence for non-neuronal localization of the TNF receptors TNFR1 to dural endothelial vascular cells and TNFR2 to dural resident macrophages as well as to some CGRP-expressing dural nerve fibers. We also demonstrate that meningeal vascular TNFR1 is co-localized with COX-1 while the perivascular TNFR2 is co-expressed with COX-2. We further report here for the first time that TNF-alpha evoked sensitization of meningeal nociceptors is dependent upon local action of cyclooxygenase (COX). Finally, we show that local application of TNF-alpha to the meninges evokes activation of the p38 MAP kinase in dural blood vessels that also express TNFR1 and that pharmacological blockade of p38 activation inhibits TNF-alpha evoked sensitization of meningeal nociceptors. Our study suggests that meningeal action of TNF-alpha could play an important role in the genesis of intracranial throbbing headaches such as migraine through a mechanism that involves at least partly activation of non-neuronal TNFR1 and TNFR2 and downstream activation of meningeal non-neuronal COX and the p38 MAP kinase.

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Section: Discussionsupporting

confidence: 89%

Tumor necrosis factor-α induces sensitization of meningeal nociceptors mediated via local COX and p38 MAP kinase actions

Zhang

Kainz

Burstein

et al. 2011

Pain

127

View full text Add to dashboard Cite

show abstract

“…To test this hypothesis, we evaluated expression of TNF‐α and IL‐6, two proinflammatory cytokines that initiate activation of other neuropathic pain‐related cytokines and growth factors 12–14. These cytokines are released by peripheral nervous system cells including macrophages, T‐cells, and Schwann cells in response to inflammation, tissue injury, and immunological reactions.…”

mentioning

confidence: 99%

Nerve compression activates selective nociceptive pathways and upregulates peripheral sodium channel expression in Schwann cells

Frieboes

Palispis

Gupta

2010

Journal Orthopaedic Research

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Chronic nerve compression (CNC) injuries, such as carpal tunnel syndrome, are common musculoskeletal conditions that affect patients with debilitating loss of sensory function and pain. Although early detection and treatment are important, our understanding of pain-related molecular mechanisms remains largely unclear. Here we investigate these mechanisms using an animal model for CNC injury. To confirm that CNC injury induces pain, we assessed expression of c-fos, a gene that is rapidly expressed in spinal sensory afferents in response to painful peripheral stimuli, and TNF-a and IL-6, two proinflammatory cytokines that are crucial to development of inflammatorymediated pain. Results show c-fos upregulation 1-2 weeks postinjury in the absence of TNF-a or IL-6 expression, indicating increased neural sensitivity without an inflammatory response. This is consistent with previous studies that showed no morphologic evidence of inflammation in the CNC model. Surprisingly, we also found de novo expression of Na V 1.8, a sodium channel linked to the development of neuropathic pain, in endoneurial Schwann cells following injury. Until now, Na V 1.8 expression was thought to be restricted to sensory neurons. CNC injury appears to be a unique model of noninflammatory neuropathic pain. Further investigation of the underlying molecular basis could yield promising targets for early diagnosis and treatment. Keywords: carpal tunnel syndrome; Schwann cell; Na V 1.8; TNF-a; IL-6, c-fos Chronic nerve compression (CNC) injuries, such as carpal tunnel syndrome, cubital tunnel syndrome, and spinal nerve root stenosis, are debilitating conditions that affect millions of Americans every year. Peripheral nerves often pass through constrained regions of the body and thus are subject to varied forms of mechanical stimulation, from shear stress to stretching and compression. CNC injuries are caused by narrowing of these nerve tunnels, limiting the nerve's movement and resulting in sustained mechanical forces, including shear stress from the nerve gliding through the restricted canal and acute pressures from direct abutment against neighboring rigid structures, as well as chronic hydrostatic pressures gradients. 1 In the early stages of injury, the most common symptoms are intermittent pain accompanied by paresthesias. As the disease progresses further, muscle atrophy and loss of motor function ensue. Current therapies are effective at ameliorating symptoms if treated early in the disease process; but prolonged nerve compression greatly decreases the chance for maximal functional recovery. [2][3][4][5] As such, early diagnosis and treatment are critical. As sensory symptoms usually present before obvious motor or electrophysiological changes, understanding the source of this pain is critical to devising methods for early-stage diagnosis and treatment. 6,7 Until recently, the molecular and cellular events leading to CNC injuries were poorly understood. This is due, in part, to the fact that excision of human tissue for investigatio...

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Neuroimmune Modulation of Synaptic Function

Pribiag

Stellwagen

2012

Neural-Immune Interactions in Brain Function and Alcohol Related Disorders

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Lipopolysaccharide-Induced Upregulation of Tumor Necrosis Factor-α (TNF-α) and TNF Receptors in Rat Sciatic Nerve

Cited by 10 publications

References 35 publications

Tumor necrosis factor-α induces sensitization of meningeal nociceptors mediated via local COX and p38 MAP kinase actions

Tumor necrosis factor-α induces sensitization of meningeal nociceptors mediated via local COX and p38 MAP kinase actions

Nerve compression activates selective nociceptive pathways and upregulates peripheral sodium channel expression in Schwann cells

Neuroimmune Modulation of Synaptic Function

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