RT Journal Article
SR Electronic
T1 Sensitisation of colonic nociceptors by TNFα is dependent on TNFR1 expression and p38 MAPK activity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.02.06.478183
DO 10.1101/2022.02.06.478183
A1 Katie H. Barker
A1 James P. Higham
A1 Luke A. Pattison
A1 Toni S. Taylor
A1 Iain P. Chessell
A1 Fraser Welsh
A1 Ewan St. J. Smith
A1 David C. Bulmer
YR 2022
UL http://biorxiv.org/content/early/2022/05/19/2022.02.06.478183.abstract
AB Visceral 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 sensitise 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 hypothesised that TNFR1-evoked p38 MAPK activity may also be responsible for TNFα sensitisation 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 sensitisation of capsaicin responses. The sensitising 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 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 sensitisation of colonic afferents, highlighting the potential utility of these drug targets for the treatment of visceral pain in GI disease.Abstract figure legend TNFα sensitised Ca2+ responses to the TRPV1 agonist capsaicin in dorsal root ganglion sensory neurons. Sensitisation was TNFR1-dependent and attenuated by inhibition of p38 MAPK. Direct Ca2+ responses to TNFα were TRPV1-and TRPA1-dependent. In ex vivo colonic afferent recordings, TNFα increased sensitivity to noxious ramp distension and capsaicin, both of which were absent in TNFR1-/- tissue or blocked by inhibition of p38 MAPK. These findings establish a role for TNFR1, p38 MAPK and TRPV1 in TNFα-mediated sensitisation of colonic afferents.Key Points SummaryTNFα sensitises sensory neurons and colonic afferents to the TRPV1 agonist capsaicin.TNFα-mediated sensitisation of sensory neurons and colonic nociceptors is dependent on TNFR1 expression.TNFα sensitisation of sensory neurons and colonic afferents to capsaicin and noxious ramp distension is abolished by inhibition of p38 MAPK.Competing Interest StatementF.W. and I.P.C. are employed by AstraZeneca.