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The Journal of Neuroscience, May 5, 2004, 24(18):4300-4312; doi:10.1523/JNEUROSCI.5679-03.2004

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Cellular/Molecular
Protease-Activated Receptor 2 Sensitizes the Capsaicin Receptor Transient Receptor Potential Vanilloid Receptor 1 to Induce Hyperalgesia

Silvia Amadesi,^1 * Jingjiang Nie,^2 * Nathalie Vergnolle,^3 * Graeme S. Cottrell,¹ Eileen F. Grady,¹ Marcello Trevisani,⁴ Chiara Manni,⁴ Pierangelo Geppetti,⁴ James A. McRoberts,² Helena Ennes,² John B. Davis,⁵ Emeran A. Mayer,² and Nigel W. Bunnett¹

¹Departments of Surgery and Physiology, University of California, San Francisco, California 94143-0660, ²Center for Neurovisceral Sciences and Women's Health, University of California Los Angeles Division of Digestive Diseases, Los Angeles, California 90095, ³Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta T2N 4N1, Canada, ⁴Department of Experimental and Clinical Medicine, University of Ferrara, 44100 Ferrara, Italy, and ⁵GlaxoSmithKline Research and Development, Department of Neurology, Gastrointestinal Centres of Excellence for Drug Discovery, Harlow GM19 5AW, United Kingdom

Inflammatory proteases (mast cell tryptase and trypsins) cleave protease-activated receptor 2 (PAR₂) 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 PAR₂-induced hyperalgesia. PAR₂ was coexpressed with TRPV1 in small- to medium-diameter neurons of the dorsal root ganglia (DRG), as determined by immunofluorescence. PAR₂ agonists increased intracellular [Ca²⁺] ([Ca²⁺]_i) in these neurons in culture, and PAR₂-responsive neurons also responded to the TRPV1 agonist capsaicin, confirming coexpression of PAR₂ and TRPV1. PAR₂ agonists potentiated capsaicin-induced increases in [Ca²⁺]_i 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 PAR₂-induced sensitization of TRPV1-mediated changes in [Ca²⁺]_i and TRPV1 currents. Activation of PAR₂ or PKC induced phosphorylation of TRPV1 in HEK cells, suggesting a direct regulation of the channel. Intraplantar injection of a PAR₂ agonist caused persistent thermal hyperalgesia that was prevented by antagonism or deletion of TRPV1. Coinjection of nonhyperalgesic doses of PAR₂ agonist and capsaicin induced hyperalgesia that was inhibited by deletion of TRPV1 or antagonism of PKC. PAR₂ 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 PAR₂ sensitize TRPV1 through PKC. Antagonism of PAR₂, TRPV1, or PKC may abrogate protease-induced thermal hyperalgesia.

Key words: protease-activated receptors; TRPV1; protein kinase C; hyperalgesia; inflammation; substance P

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Received Dec 23, 2003; revised February 11, 2004; accepted March 18, 2004.

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