title: Involvement of transient receptor potential vanilloid 1 receptors in protease-activated receptor-2-induced joint inflammation and nociception.
abstract: 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.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, H-7624 Pécs, Szigeti u. 12., Hungary. zsuzsanna.helyes@aok.pte.hu
authors.forename: Zs
authors.initials: Z
authors.lastname: Helyes
authors.forename: K
authors.initials: K
authors.lastname: Sándor
authors.forename: E
authors.initials: E
authors.lastname: Borbély
authors.forename: V
authors.initials: V
authors.lastname: Tékus
authors.forename: E
authors.initials: E
authors.lastname: Pintér
authors.forename: K
authors.initials: K
authors.lastname: Elekes
authors.forename: D M
authors.initials: DM
authors.lastname: Tóth
authors.forename: J
authors.initials: J
authors.lastname: Szolcsányi
authors.forename: J J
authors.initials: JJ
authors.lastname: McDougall
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000201:enzymology*; D001835:Body Weight / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation / Q000502:physiology; D005528:Foot / Q000473:pathology; D006614:Hindlimb / Q000473:pathology; D006930:Hyperalgesia / Q000201:enzymology; D007270:Injections, Intra-Articular; D008297:Male; D008465:Mechanoreceptors / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000201:enzymology*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D044464:Receptor, PAR-2 / Q000502:physiology*; D050916:TRPV Cation Channels / Q000502:physiology*
chemical_list: D000813:Anilides; D002934:Cinnamates; D016207:Cytokines; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D009842:Oligopeptides; D044464:Receptor, PAR-2; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C099570:seryl-leucyl-isoleucyl-glycyl-arginyl-leucine