Involvement of transient receptor potential vanilloid 1 receptors in protease-activated receptor-2-induced joint inflammation and nociception

Eur J Pain. 2010 Apr;14(4):351-8. doi: 10.1016/j.ejpain.2009.07.005. Epub 2009 Aug 15.


Protease-activated receptor-2 (PAR-2) is a G-protein-coupled receptor activated through proteolytic cleavage. It is localized on epithelial, endothelial and inflammatory cells, as well as on transient receptor potential vanilloid 1 (TRPV1) receptor-expressing neurones. It plays an important role in inflammatory/nociceptive processes. Since there are few reports concerning PAR-2 function in joints, the effects of intraarticular PAR-2 activation on joint pain and inflammation were studied. Secondary hyperalgesia/allodynia, spontaneous weight distribution, swelling and inflammatory cytokine production were measured and the involvement of TRPV1 ion channels was investigated in rats and mice. Injection of the PAR-2 receptor agonist SLIGRL-NH(2) into the knee decreased touch sensitivity and weight bearing of the ipsilateral hindlimb in both species. Secondary mechanical allodynia/hyperalgesia and impaired weight distribution were significantly reduced by the TRPV1 antagonist SB366791 in rats and by the genetic deletion of this receptor in mice. PAR-2 activation did not cause significant joint swelling, but increased IL-1beta concentration which was not influenced by the lack of the TRPV1 channel. For comparison, intraplantar SLIGRL-NH(2) evoked similar primary mechanical hyperalgesia and impaired weight distribution in both WT and TRPV1 deficient mice, but oedema was smaller in the knockouts. The inactive peptide, LRGILS-NH(2), injected into either site did not induce any inflammatory or nociceptive changes. These data provide evidence for a significant role of TRPV1 receptors in secondary mechanical hyperalgesia/allodynia and spontaneous pain induced by PAR-2 receptor activation in the knee joint. Although intraplantar PAR-2 activation-induced oedema is also TRPV1 receptor-mediated, primary mechanical hyperalgesia, impaired weight distribution and IL-1beta production are independent of this channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / pharmacology
  • Animals
  • Arthritis / chemically induced
  • Arthritis / enzymology*
  • Body Weight / drug effects
  • Cinnamates / pharmacology
  • Cytokines / biosynthesis
  • Enzyme Activation / physiology
  • Foot / pathology
  • Hindlimb / pathology
  • Hyperalgesia / enzymology
  • Injections, Intra-Articular
  • Male
  • Mechanoreceptors / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Oligopeptides / administration & dosage
  • Oligopeptides / pharmacology
  • Pain / chemically induced
  • Pain / enzymology*
  • Pain Measurement / drug effects
  • Pain Threshold / drug effects
  • Rats
  • Rats, Wistar
  • Receptor, PAR-2 / physiology*
  • TRPV Cation Channels / physiology*


  • Anilides
  • Cinnamates
  • Cytokines
  • N-(3-methoxyphenyl)-4-chlorocinnamanilide
  • Oligopeptides
  • Receptor, PAR-2
  • TRPV Cation Channels
  • Trpv1 protein, rat
  • seryl-leucyl-isoleucyl-glycyl-arginyl-leucine