Premium
Protease‐activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice
Author(s) -
Grant Andrew D.,
Cottrell Graeme S.,
Amadesi Silvia,
Trevisani Marcello,
Nicoletti Paola,
Materazzi Serena,
Altier Christophe,
Cenac Nicolas,
Zamponi Gerald W.,
BautistaCruz Francisco,
Lopez Carlos Barajas,
Joseph Elizabeth K.,
Levine Jon D.,
Liedtke Wolfgang,
Vanner Stephen,
Vergnolle Nathalie,
Geppetti Pierangelo,
Bunnett Nigel W.
Publication year - 2007
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2006.121111
Subject(s) - hyperalgesia , trpv4 , transient receptor potential channel , agonist , calcitonin gene related peptide , chemistry , sensitization , trpv1 , protease activated receptor 2 , pharmacology , receptor , nociception , medicine , endocrinology , neuroscience , neuropeptide , biology , biochemistry , enzyme linked receptor
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 (PAR 2 ) on afferent nerves to cause mechanical hyperalgesia in the skin and intestine by unknown mechanisms. We hypothesized that PAR 2 ‐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 PAR 2 , substance P (SP) and calcitonin gene‐related peptide (CGRP), mediators of pain transmission. In PAR 2 ‐expressing cell lines that either naturally expressed TRPV4 (bronchial epithelial cells) or that were transfected to express TRPV4 (HEK cells), pretreatment with a PAR 2 agonist enhanced Ca 2+ and current responses to the TRPV4 agonists phorbol ester 4α‐phorbol 12,13‐didecanoate (4αPDD) and hypotonic solutions. PAR 2 ‐agonist similarly sensitized TRPV4 Ca 2+ signals and currents in DRG neurons. Antagonists of phospholipase Cβ and protein kinases A, C and D inhibited PAR 2 ‐induced sensitization of TRPV4 Ca 2+ signals and currents. 4αPDD and hypotonic solutions stimulated SP and CGRP release from dorsal horn of rat spinal cord, and pretreatment with PAR 2 agonist sensitized TRPV4‐dependent peptide release. Intraplantar injection of PAR 2 agonist caused mechanical hyperalgesia in mice and sensitized pain responses to the TRPV4 agonists 4αPDD and hypotonic solutions. Deletion of TRPV4 prevented PAR 2 agonist‐induced mechanical hyperalgesia and sensitization. This novel mechanism, by which PAR 2 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.