{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:10:44Z","timestamp":1791216644716,"version":"4.1.0"},"reference-count":64,"publisher":"Society for Neuroscience","issue":"18","license":[{"start":{"date-parts":[[2004,11,5]],"date-time":"2004-11-05T00:00:00Z","timestamp":1099612800000},"content-version":"vor","delay-in-days":184,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2004,5,5]]},"abstract":"<jats:p>Inflammatory proteases (mast cell tryptase and trypsins) cleave protease-activated receptor 2 (PAR<jats:sub>2<\/jats:sub>) on spinal afferent neurons and cause persistent inflammation and hyperalgesia by unknown mechanisms. We determined whether transient receptor potential vanilloid receptor 1 (TRPV1), a cation channel activated by capsaicin, protons, and noxious heat, mediates PAR<jats:sub>2<\/jats:sub>-induced hyperalgesia. PAR<jats:sub>2<\/jats:sub>was coexpressed with TRPV1 in small- to medium-diameter neurons of the dorsal root ganglia (DRG), as determined by immunofluorescence. PAR<jats:sub>2<\/jats:sub>agonists increased intracellular [Ca<jats:sup>2+<\/jats:sup>] ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) in these neurons in culture, and PAR<jats:sub>2<\/jats:sub>-responsive neurons also responded to the TRPV1 agonist capsaicin, confirming coexpression of PAR<jats:sub>2<\/jats:sub>and TRPV1. PAR<jats:sub>2<\/jats:sub>agonists potentiated capsaicin-induced increases in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>in TRPV1-transfected human embryonic kidney (HEK) cells and DRG neurons and potentiated capsaicin-induced currents in DRG neurons. Inhibitors of phospholipase C and protein kinase C (PKC) suppressed PAR<jats:sub>2<\/jats:sub>-induced sensitization of TRPV1-mediated changes in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>and TRPV1 currents. Activation of PAR<jats:sub>2<\/jats:sub>or PKC induced phosphorylation of TRPV1 in HEK cells, suggesting a direct regulation of the channel. Intraplantar injection of a PAR<jats:sub>2<\/jats:sub>agonist caused persistent thermal hyperalgesia that was prevented by antagonism or deletion of TRPV1. Coinjection of nonhyperalgesic doses of PAR<jats:sub>2<\/jats:sub>agonist and capsaicin induced hyperalgesia that was inhibited by deletion of TRPV1 or antagonism of PKC. PAR<jats:sub>2<\/jats:sub>activation also potentiated capsaicin-induced release of substance P and calcitonin gene-related peptide from superfused segments of the dorsal horn of the spinal cord, where they mediate hyperalgesia. We have identified a novel mechanism by which proteases that activate PAR<jats:sub>2<\/jats:sub>sensitize TRPV1 through PKC. Antagonism of PAR<jats:sub>2<\/jats:sub>, TRPV1, or PKC may abrogate protease-induced thermal hyperalgesia.<\/jats:p>","DOI":"10.1523\/jneurosci.5679-03.2004","type":"journal-article","created":{"date-parts":[[2004,5,5]],"date-time":"2004-05-05T19:41:22Z","timestamp":1083786082000},"page":"4300-4312","source":"Crossref","is-referenced-by-count":360,"title":["Protease-Activated Receptor 2 Sensitizes the Capsaicin Receptor Transient Receptor Potential Vanilloid Receptor 1 to Induce Hyperalgesia"],"prefix":"10.1523","volume":"24","author":[{"given":"Silvia","family":"Amadesi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjiang","family":"Nie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Vergnolle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme 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