Antagonism of the proinflammatory and pronociceptive actions of canonical and biased agonists of protease-activated receptor-2

Lieu, T., Savage, E., Zhao, P., Edgington-Mitchell, L., Barlow, N., Bron, R., Poole, D. P., Mclean, P., Lohman, R. -J., Fairlie, D. P. and 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: 2752-2765. doi:10.1111/bph.13554

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Author Lieu, 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.
Title Antagonism of the proinflammatory and pronociceptive actions of canonical and biased agonists of protease-activated receptor-2
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 1476-5381
Publication date 2016-09-01
Sub-type Article (original research)
DOI 10.1111/bph.13554
Open Access Status DOI
Volume 173
Issue 18
Start page 2752
End page 2765
Total pages 14
Place of publication Chichester, West Sussex, United Kingdom
Publisher John Wiley & Sons
Language eng
Formatted abstract
Background 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 [Ca2+]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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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Created: Fri, 09 Sep 2016, 21:25:35 EST by Susan Allen on behalf of Learning and Research Services (UQ Library)