ArticleBritish journal of pharmacology2016
Antagonism of the proinflammatory and pronociceptive actions of canonical and biased agonists of protease-activated receptor-2.
Article in British journal of pharmacology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 25 citations in OpenAlex.
- Systematic identification of p11 as a signaling modulator across the GPCRome.Science advances · 2026Article
- MMP1 and PRSS23 induce PARCommunications biology · 2026Article
- Protease-activated receptors act as a liaison between metabolism and inflammation.Inflammopharmacology · 2026Review
- Modulation of Nociceptive Ion Channels by Protease-Activated Receptor-2 in Inflammatory Pain: Molecular Mechanisms and Therapeutic Potential.International journal of molecular sciences · 2026Review
- Electrophysiological and Proteomic Evidence of Protease-Mediated Pro-nociceptive Signaling in Inflammatory Bowel Disease Patients.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Probing the activity of cysteine cathepsins in inflammatory bowel diseases.Scientific reports · 2025Article
- Validity of Plasma Neuropeptide Y in Combination with Clinical Factors in Predicting Neuralgia Following Herpes Zoster.International journal of general medicine · 2024Article
- An update on mechanisms of pruritus and their potential treatment in primary cutaneous T-cell lymphoma.Clinical and experimental medicine · 2023Review
- Electroacupuncture Relieves Visceral Hypersensitivity via Balancing PAR2 and PAR4 in the Descending Pain Modulatory System of Goats.Brain sciences · 2023Article
- β-Arrestin-biased proteinase-activated receptor-2 antagonist C781 limits allergen-induced airway hyperresponsiveness and inflammation.British journal of pharmacology · 2023Article
- Proteinase-activated receptor-2 antagonist C391 inhibits Alternaria-induced airway epithelial signalling and asthma indicators in acute exposure mouse models.British journal of pharmacology · 2022Article
- Cathepsin S is a novel target for age-related dry eye.Experimental eye research · 2022Article
- PAR-2-activated secretion by airway gland serous cells: role for CFTR and inhibition byAmerican journal of physiology. Lung cellular and molecular physiology · 2021Article
- Spinal PAR2 Activation Contributes to Hypersensitivity Induced by Peripheral Inflammation in Rats.International journal of molecular sciences · 2021Article
- Legumain Induces Oral Cancer Pain by Biased Agonism of Protease-Activated Receptor-2.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- Application of a chemical probe to detect neutrophil elastase activation during inflammatory bowel disease.Scientific reports · 2019Article
- Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases.Thrombosis journal · 2019Review
- Protease activated receptor 2 (PAR2) activation causes migraine-like pain behaviors in mice.Cephalalgia : an international journal of headache · 2019Article
- Cathepsin S Alters the Expression of Pro-Inflammatory Cytokines and MMP-9, Partially through Protease-Activated Receptor-2, in Human Corneal Epithelial Cells.International journal of molecular sciences · 2018Article
- Protease-activated receptor-2 in endosomes signals persistent pain of irritable bowel syndrome.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
background and purposeDiverse 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
resultsIntraplantar 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.