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dc.contributor.authorBarker, Katie H
dc.contributor.authorHigham, James P
dc.contributor.authorPattison, Luke A
dc.contributor.authorTaylor, Toni S
dc.contributor.authorChessell, Iain P
dc.contributor.authorWelsh, Fraser
dc.contributor.authorSmith, Ewan St J
dc.contributor.authorBulmer, David C
dc.date.accessioned2022-07-22T08:00:12Z
dc.date.available2022-07-22T08:00:12Z
dc.date.issued2022-08
dc.date.submitted2022-05-21
dc.identifier.issn0022-3751
dc.identifier.othertjp15177
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/339392
dc.description.abstractVisceral pain is a leading cause of morbidity in gastrointestinal diseases, which is exacerbated by the gut-related side-effects of many analgesics. New treatments are needed and further understanding of the mediators and mechanisms underpinning visceral nociception in disease states is required to facilitate this. The pro-inflammatory cytokine TNFα is linked to pain in both patients with inflammatory bowel disease and irritable bowel syndrome, and has been shown to sensitize colonic sensory neurons. Somatic, TNFα-triggered thermal and mechanical hypersensitivity is mediated by TRPV1 signalling and p38 MAPK activity respectively, downstream of TNFR1 receptor activation. We therefore hypothesized that TNFR1-evoked p38 MAPK activity may also be responsible for TNFα sensitization of colonic afferent responses to the TRPV1 agonist capsaicin, and noxious distension of the bowel. Using Ca2+ imaging of dorsal root ganglion sensory neurons, we observed TNFα-mediated increases in intracellular [Ca2+ ] and sensitization of capsaicin responses. The sensitizing effects of TNFα were dependent on TNFR1 expression and attenuated by p38 MAPK inhibition. Consistent with these findings, ex vivo colonic afferent fibre recordings demonstrated an enhanced response to noxious ramp distention of the bowel and bath application of capsaicin following TNFα pre-treatment. Responses were reversed by p38 MAPK inhibition and absent in tissue from TNFR1 knockout mice. Our findings demonstrate a contribution of TNFR1, p38 MAPK and TRPV1 to TNFα-induced sensitization of colonic afferents, highlighting the potential utility of these drug targets for the treatment of visceral pain in gastrointestinal disease. KEY POINTS: The pro-inflammatory cytokine TNFα is elevated in gastrointestinal disease and sensitizes colonic afferents via modulation of TRPA1 and NaV 1.8 activity. We further develop this understanding by demonstrating a role for p38 MAPK and TRPV1 in TNFα-mediated colonic afferent sensitization. Specifically, we show that: TNFα sensitizes sensory neurons and colonic afferents to the TRPV1 agonist capsaicin. TNFα-mediated sensitization of sensory neurons and colonic nociceptors is dependent on TNFR1 expression. TNFα sensitization of sensory neurons and colonic afferents to capsaicin and noxious ramp distension is abolished by inhibition of p38 MAPK. Collectively these data support the utility of targeting TNFα, TNFR1 and their downstream signalling via p38 MAPK for the treatment of visceral pain in gastrointestinal disease.
dc.languageen
dc.publisherWiley
dc.subjectResearch Article
dc.subjectNeuroscience
dc.subjectcapsaicin
dc.subjectinflammatory bowel disease
dc.subjectirritable bowel syndrome
dc.subjectnociception
dc.subjectp38 MAPK
dc.subjecttumour necrosis factor‐alpha
dc.subjectTRPV1
dc.subjectvisceral pain
dc.titleSensitization of colonic nociceptors by TNFα is dependent on TNFR1 expression and p38 MAPK activity.
dc.typeArticle
dc.date.updated2022-07-22T08:00:11Z
prism.publicationNameJ Physiol
dc.identifier.doi10.17863/CAM.86802
dcterms.dateAccepted2022-06-28
rioxxterms.versionofrecord10.1113/JP283170
rioxxterms.versionAO
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidBarker, Katie H [0000-0002-8601-4416]
dc.contributor.orcidBulmer, David C [0000-0002-4703-7877]
dc.identifier.eissn1469-7793
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/M011194/1)
cam.issuedOnline2022-07-21
datacite.issupplementedby.urlhttps://doi.org/10.17863/CAM.81112


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