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dc.contributor.authorLieu, T
dc.contributor.authorSavage, E
dc.contributor.authorZhao, P
dc.contributor.authorEdgington-Mitchell, L
dc.contributor.authorBarlow, N
dc.contributor.authorBron, R
dc.contributor.authorPoole, DP
dc.contributor.authorMcLean, P
dc.contributor.authorLohman, R-J
dc.contributor.authorFairlie, DP
dc.contributor.authorBunnett, NW
dc.date.accessioned2021-02-05T00:36:25Z
dc.date.available2021-02-05T00:36:25Z
dc.date.issued2016-09-01
dc.identifier.citationLieu, T., Savage, E., Zhao, P., Edgington-Mitchell, L., Barlow, N., Bron, R., Poole, D. P., McLean, P., Lohman, R. -J., Fairlie, D. P. & Bunnett, N. W. (2016). Antagonism of the proinflammatory and pronociceptive actions of canonical and biased agonists of protease-activated receptor-2. BRITISH JOURNAL OF PHARMACOLOGY, 173 (18), pp.2752-2765. https://doi.org/10.1111/bph.13554.
dc.identifier.issn0007-1188
dc.identifier.urihttp://hdl.handle.net/11343/260074
dc.description.abstractBACKGROUND AND PURPOSE: Diverse proteases cleave protease-activated receptor-2 (PAR2) on primary sensory neurons and epithelial cells to evoke pain and inflammation. Trypsin and tryptase activate PAR2 by a canonical mechanism that entails cleavage within the extracellular N-terminus revealing a tethered ligand that activates the cleaved receptor. Cathepsin-S and elastase are biased agonists that cleave PAR2 at different sites to activate distinct signalling pathways. Although PAR2 is a therapeutic target for inflammatory and painful diseases, the divergent mechanisms of proteolytic activation complicate the development of therapeutically useful antagonists. EXPERIMENTAL APPROACH: We investigated whether the PAR2 antagonist GB88 inhibits protease-evoked activation of nociceptors and protease-stimulated oedema and hyperalgesia in rodents. KEY RESULTS: Intraplantar injection of trypsin, cathespsin-S or elastase stimulated mechanical and thermal hyperalgesia and oedema in mice. Oral GB88 or par2 deletion inhibited the algesic and proinflammatory actions of all three proteases, but did not affect basal responses. GB88 also prevented pronociceptive and proinflammatory effects of the PAR2-selective agonists 2-furoyl-LIGRLO-NH2 and AC264613. GB88 did not affect capsaicin-evoked hyperalgesia or inflammation. Trypsin, cathepsin-S and elastase increased [Ca(2+) ]i in rat nociceptors, which expressed PAR2. GB88 inhibited this activation of nociceptors by all three proteases, but did not affect capsaicin-evoked activation of nociceptors or inhibit the catalytic activity of the three proteases. CONCLUSIONS AND IMPLICATIONS: GB88 inhibits the capacity of canonical and biased protease agonists of PAR2 to cause nociception and inflammation.
dc.languageEnglish
dc.publisherWILEY-BLACKWELL
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
dc.titleAntagonism of the proinflammatory and pronociceptive actions of canonical and biased agonists of protease-activated receptor-2
dc.typeJournal Article
dc.identifier.doi10.1111/bph.13554
melbourne.affiliation.departmentAnatomy and Neuroscience
melbourne.affiliation.departmentPharmacology and Therapeutics
melbourne.affiliation.departmentBiochemistry and Molecular Biology
melbourne.affiliation.facultyMedicine, Dentistry & Health Sciences
melbourne.source.titleBritish Journal of Pharmacology
melbourne.source.volume173
melbourne.source.issue18
melbourne.source.pages2752-2765
dc.rights.licenseCC BY-NC-ND
melbourne.elementsid1089515
melbourne.contributor.authorPoole, Daniel
melbourne.contributor.authorLohman, Rink-Jan
melbourne.contributor.authorBunnett, Nigel
melbourne.contributor.authorEdgington-Mitchell, Laura
dc.identifier.eissn1476-5381
melbourne.accessrightsOpen Access


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