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This Article Full Text Full Text (PDF) All Versions of this Article: 578/3/715    most recent jphysiol.2006.121111v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grant, A. D. Articles by Bunnett, N. W. Search for Related Content PubMed PubMed Citation Articles by Grant, A. D. Articles by Bunnett, N. W. Related Collections Neuroscience

¹ Departments of Surgery and Physiology, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0660, USA
² Department of Critical Care Medicine and Surgery, University of Florence, Florence, Italy
³ Department of Physiology and Biophysics⁴Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
⁵ Instituto Potosino de Investigacion Cientifica y Tecnologica San Luis Potosi, SLP, Mexico
⁶ Gastrointestinal Diseases Research Unit, Division of Gastroenterology, Queen's University, Kingston, Ontario, Canada
⁷ Departments of Oral and Maxofacial Surgery and Medicine, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0660, USA
⁸ Department of Medicine and Neurobiology, Duke University Medical Center 2900, Durham, NC 27710, USA

Exacerbated sensitivity to mechanical stimuli that are normally innocuous or mildly painful (mechanical allodynia and hyperalgesia) occurs during inflammation and underlies painful diseases. Proteases that are generated during inflammation and disease cleave protease-activated receptor 2 (PAR₂) on afferent nerves to cause mechanical hyperalgesia in the skin and intestine by unknown mechanisms. We hypothesized that PAR₂-mediated mechanical hyperalgesia requires sensitization of the ion channel transient receptor potential vanilloid 4 (TRPV4). Immunoreactive TRPV4 was coexpressed by rat dorsal root ganglia (DRG) neurons with PAR₂, substance P (SP) and calcitonin gene-related peptide (CGRP), mediators of pain transmission. In PAR₂-expressing cell lines that either naturally expressed TRPV4 (bronchial epithelial cells) or that were transfected to express TRPV4 (HEK cells), pretreatment with a PAR₂ agonist enhanced Ca²⁺ and current responses to the TRPV4 agonists phorbol ester 4-phorbol 12,13-didecanoate (4PDD) and hypotonic solutions. PAR₂-agonist similarly sensitized TRPV4 Ca²⁺ signals and currents in DRG neurons. Antagonists of phospholipase C and protein kinases A, C and D inhibited PAR₂-induced sensitization of TRPV4 Ca²⁺ signals and currents. 4PDD and hypotonic solutions stimulated SP and CGRP release from dorsal horn of rat spinal cord, and pretreatment with PAR₂ agonist sensitized TRPV4-dependent peptide release. Intraplantar injection of PAR₂ agonist caused mechanical hyperalgesia in mice and sensitized pain responses to the TRPV4 agonists 4PDD and hypotonic solutions. Deletion of TRPV4 prevented PAR₂ agonist-induced mechanical hyperalgesia and sensitization. This novel mechanism, by which PAR₂ activates a second messenger to sensitize TRPV4-dependent release of nociceptive peptides and induce mechanical hyperalgesia, may underlie inflammatory hyperalgesia in diseases where proteases are activated and released.

(Received 12 September 2006; accepted after revision 21 November 2006; first published online 23 November 2006)
Corresponding author N. W. Bunnett: UCSF, 513 Parnassus Ave., Room S1268, San Francisco, CA 94143-0660, USA. Email: nigel.bunnett{at}ucsf.edu

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