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Received April 13, 2006
Revised May 16, 2006
Accepted after revision June 20, 2006
- AND A-DEPENDENT MECHANISMS IN RATS AND MICE
1 University of California, San Francisco
2 UCSF
3 U Calgary
4 Instituto Potosino
5 Queen's University
* To whom correspondence should be addressed. E-mail: nigelb{at}itsa.ucsf.edu.
Proteases that are released during inflammation and injury cleave protease-activated receptor 2 (PAR2) on primary afferent neurons to cause neurogenic inflammation and hyperalgesia. PAR2-induced thermal hyperalgesia depends on sensitization of transient receptor potential vanilloid receptor 1 (TRPV1), which is gated by capsaicin, protons and noxious heat. However, the signaling mechanisms by which PAR2 sensitizes TRPV1 are not fully characterized. Using immunofluorescence and confocal microscopy, we observed that PAR2 was colocalized with protein kinase (PK) C
and PKA in a subset of dorsal root ganglia neurons in rats, and that PAR2 agonists promoted translocation of PKC and PKA catalytic subunit from the cytosol to the plasma membrane of cultured neurons and HEK293 cells. Subcellular fractionation and Western blotting confirmed this redistribution of kinases, which is indicative of activation. Although PAR2 couples to phospholipase C
, leading to stimulation of PKC, we also observed that PAR2 agonists increased cAMP generation in neurons and HEK293 cells, which would activate PKA. PAR2 agonists enhanced capsaicin-stimulated increases in [Ca2+]i and whole-cell currents in HEK293 cells, indicating TRPV1 sensitization. The combined intraplantar injection of non-algesic doses of PAR2 agonists and capsaicin decreased the latency of paw withdrawal to radiant heat in mice, indicative of thermal hyperalgesia. Antagonists of PKC and PKA prevented sensitization of TRPV1 Ca2+ signals and currents in HEK293 cells, and suppressed thermal hyperalgesia in mice. Thus, PAR2 activates PKC and PKA in sensory neurons and thereby sensitizes TRPV1 to cause thermal hyperalgesia. These mechanisms may underlie inflammatory pain, where multiple proteases are generated and released.
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