RGD Reference Report - Tumor necrosis factor-alpha induces sensitization of meningeal nociceptors mediated via local COX and p38 MAP kinase actions. - Rat Genome Database

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

Authors: Zhang, XC  Kainz, V  Burstein, R  Levy, D 
Citation: Zhang XC, etal., Pain. 2011 Jan;152(1):140-9. Epub 2010 Oct 30.
RGD ID: 5131274
Pubmed: PMID:21036476   (View Abstract at PubMed)
PMCID: PMC3391748   (View Article at PubMed Central)
DOI: DOI:10.1016/j.pain.2010.10.002   (Journal Full-text)

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 part activation of non-neuronal TNFR1 and TNFR2 and downstream activation of meningeal non-neuronal COX and the p38 MAP kinase.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Headache  IMP 5131274human protein in rat modelRGD 
Headache  ISOTNFRSF1B (Homo sapiens)5131274; 5131274human protein in rat modelRGD 

Objects Annotated

Genes (Rattus norvegicus)
Tnfrsf1b  (TNF receptor superfamily member 1B)

Genes (Mus musculus)
Tnfrsf1b  (tumor necrosis factor receptor superfamily, member 1b)

Genes (Homo sapiens)
TNFRSF1B  (TNF receptor superfamily member 1B)


Additional Information