title: Triggering of proteinase-activated receptor 4 leads to joint pain and inflammation in mice.
abstract: OBJECTIVE
  To investigate the role of proteinase-activated receptor 4 (PAR-4) in mediating joint inflammation and pain in mice.
  
  
  METHODS
  Knee joint blood flow, edema, and pain sensitivity (as induced by thermal and mechanical stimuli) were assessed in C57BL/6 mice following intraarticular injection of either the selective PAR-4 agonist AYPGKF-NH(2) or the inactive control peptide YAPGKF-NH(2). The mechanism of action of AYPGKF-NH(2) was examined by pretreatment of each mouse with either the PAR-4 antagonist pepducin P4pal-10 or the bradykinin antagonist HOE 140. Finally, the role of PAR-4 in mediating joint inflammation was tested by pretreating mice with acutely inflamed knees with pepducin P4pal-10.
  
  
  RESULTS
  PAR-4 activation caused a long-lasting increase in joint blood flow and edema formation, which was not seen following injection of the control peptide. The PAR-4-activating peptide was also found to be pronociceptive in the joint, where it enhanced sensitivity to a noxious thermal stimulus and caused mechanical allodynia and hyperalgesia. The proinflammatory and pronociceptive effects of AYPGKF-NH(2) could be inhibited by pepducin P4pal-10 and HOE 140. Finally, pepducin P4pal-10 ameliorated the clinical and physiologic signs of acute joint inflammation.
  
  
  CONCLUSIONS
  This study demonstrates that local activation of PAR-4 leads to proinflammatory changes in the knee joint that are dependent on the kallikrein-kinin system. We also show for the first time that PARs are involved in the modulation of joint pain, with PAR-4 being pronociceptive in this tissue. Thus, blockade of articular PAR-4 may be a useful means of controlling joint inflammation and pain.
authors.affiliation: University of Calgary, Calgary, Alberta, Canada. mcdougaj@ucalgary.ca
authors.forename: Jason J
authors.initials: JJ
authors.lastname: McDougall
authors.forename: Chunfen
authors.initials: C
authors.lastname: Zhang
authors.forename: Laurie
authors.initials: L
authors.lastname: Cellars
authors.forename: Eva
authors.initials: E
authors.lastname: Joubert
authors.forename: Chantelle M
authors.initials: CM
authors.lastname: Dixon
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vergnolle
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology; D018771:Arthralgia / Q000378:metabolism*; D001168:Arthritis / Q000209:etiology* / Q000378:metabolism*; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists; D004195:Disease Models, Animal; D004487:Edema / Q000378:metabolism; D007270:Injections, Intra-Articular; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D043782:Receptor, Bradykinin B2 / Q000378:metabolism; D044462:Receptors, Proteinase-Activated / Q000819:agonists / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology
chemical_list: C482003:AYPGKG-NH(2); D000894:Anti-Inflammatory Agents, Non-Steroidal; D065094:Bradykinin B2 Receptor Antagonists; D009842:Oligopeptides; D043782:Receptor, Bradykinin B2; D044462:Receptors, Proteinase-Activated; C524864:palmitoyl-seryl-glycyl-arginyl-arginyl-tyrosyl-glycyl-histidyl-alanyl-leucyl-arginine; C481942:protease-activated receptor 4, mouse; C065679:icatibant; D001920:Bradykinin