title: Activation of PAR(2)  receptors sensitizes primary afferents and causes leukocyte rolling and adherence in the rat knee joint.
abstract: OBJECTIVE
  The PAR(2) receptors are involved in chronic arthritis by mechanisms that are as yet unclear. Here, we examined PAR(2) activation in the rat knee joint.
  
  
  METHODS
  PAR(2) in rat knee joint dorsal root ganglia (DRG) cells at L3-L5, retrogradely labelled with Fluoro-gold (FG) were demonstrated immunohistochemically. Electrophysiological recordings from knee joint nerve fibres in urethane anaesthetized Wistar rats assessed the effects of stimulating joint PAR(2) with its activating peptide, 2-furoyl-LIGRLO-NH(2) (1-100 nmol·100 μL(-1) , via close intra-arterial injection). Fibre firing rate was recorded during joint rotations before and 15 min after administration of PAR(2) activating peptide or control peptide. Leukocyte kinetics in the synovial vasculature upon PAR(2) activation were followed by intravital microscopy for 60 min after perfusion of 2-furoyl-LIGRLO-NH(2) or control peptide. Roles for transient receptor potential vanilloid-1 (TRPV1) or neurokinin-1 (NK(1) ) receptors in the PAR(2) responses were assessed using the selective antagonists, SB366791 and RP67580 respectively.
  
  
  RESULTS
  PAR(2) were expressed in 59 ± 5% of FG-positive DRG cells; 100 nmol 2-furoyl-LIGRLO-NH(2) increased joint fibre firing rate during normal and noxious rotation, maximal at 3 min (normal; 110 ± 43%, noxious; 90 ± 31%). 2-Furoyl-LIGRLO-NH(2) also significantly increased leukocyte rolling and adhesion over 60 min. All these effects were blocked by pre-treatment with SB366791 and RP67580 (P < 0.05 compared with 2-furoyl-LIGRLO-NH(2) alone).
  
  
  CONCLUSIONS
  PAR(2) receptors play an acute inflammatory role in the knee joint via TRPV1- and NK(1) -dependent mechanisms involving both PAR(2) -mediated neuronal sensitization and leukocyte trafficking.
authors: Department of Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada.
authors: F A
authors: FA
authors: Russell
authors: N
authors: N
authors: Schuelert
authors: V E
authors: VE
authors: Veldhoen
authors: M D
authors: MD
authors: Hollenberg
authors: J J
authors: JJ
authors: McDougall
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001168:Arthritis / Q000503:physiopathology; D002448:Cell Adhesion; D002934:Cinnamates / Q000494:pharmacology; D054833:Isoindoles / Q000494:pharmacology; D007719:Knee Joint / Q000294:innervation / Q000502:physiology*; D036904:Leukocyte Rolling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064729:Neurokinin-1 Receptor Antagonists; D009475:Neurons, Afferent / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044464:Receptor, PAR-2 / Q000819:agonists / Q000502:physiology*; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C487404:2-furoyl-LIGRLO-amide; D000813:Anilides; D002934:Cinnamates; D054833:Isoindoles; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D064729:Neurokinin-1 Receptor Antagonists; D009842:Oligopeptides; D044464:Receptor, PAR-2; D018040:Receptors, Neurokinin-1; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one