title: Paradoxical effects of the cannabinoid CB2 receptor agonist GW405833 on rat osteoarthritic knee joint pain.
abstract: OBJECTIVE
  The present study examined whether local administration of the cannabinoid-2 (CB(2)) receptor agonist GW405833 could modulate joint nociception in control rat knee joints and in an animal model of osteoarthritis (OA).
  
  
  METHODS
  OA was induced in male Wistar rats by intra-articular injection of sodium monoiodo-acetate with a recovery period of 14 days. Immunohistochemistry was used to evaluate the expression of CB(2) and transient receptor potential vanilloid channel-1 (TRPV1) receptors in the dorsal root ganglion (DRG) and synovial membrane of sham- and sodium mono-iodoacetate (MIA)-treated animals. Electrophysiological recordings were made from knee joint primary afferents in response to rotation of the joint both before and following close intra-arterial injection of different doses of GW405833. The effect of intra-articular GW405833 on joint pain perception was determined by hindlimb incapacitance. An in vitro neuronal release assay was used to see if GW405833 caused release of an inflammatory neuropeptide (calcitonin gene-related peptide - CGRP).
  
  
  RESULTS
  CB(2) and TRPV1 receptors were co-localized in DRG neurons and synoviocytes in both sham- and MIA-treated animals. Local application of the GW405833 significantly reduced joint afferent firing rate by up to 31% in control knees. In OA knee joints, however, GW405833 had a pronounced sensitising effect on joint mechanoreceptors. Co-administration of GW405833 with the CB(2) receptor antagonist AM630 or pre-administration of the TRPV1 ion channel antagonist SB366791 attenuated the sensitising effect of GW405833. In the pain studies, intra-articular injection of GW405833 into OA knees augmented hindlimb incapacitance, but had no effect on pain behaviour in saline-injected control joints. GW405833 evoked increased CGRP release via a TRPV1 channel-dependent mechanism.
  
  
  CONCLUSIONS
  These data indicate that GW405833 reduces the mechanosensitivity of afferent nerve fibres in control joints but causes nociceptive responses in OA joints. The observed pro-nociceptive effect of GW405833 appears to involve TRPV1 receptors.
authors.affiliation: Department of Physiology & Pharmacology, University of Calgary, 3330 Hospital Drive NW Calgary, AB T2N 4N1, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Schuelert
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.forename: A J
authors.initials: AJ
authors.lastname: Mogg
authors.forename: L M
authors.initials: LM
authors.lastname: Broad
authors.forename: D L
authors.initials: DL
authors.lastname: Hepburn
authors.forename: E S
authors.initials: ES
authors.lastname: Nisenbaum
authors.forename: M P
authors.initials: MP
authors.lastname: Johnson
authors.forename: J J
authors.initials: JJ
authors.lastname: McDougall
mesh_terms: D000818:Animals; D002186:Cannabinoids / Q000032:analysis; D004195:Disease Models, Animal; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000378:metabolism; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology*; D007270:Injections, Intra-Articular; D007719:Knee Joint / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D020370:Osteoarthritis, Knee / Q000150:complications* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D051381:Rats; D017208:Rats, Wistar; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013583:Synovial Membrane / Q000378:metabolism; D050916:TRPV Cation Channels / Q000032:analysis
chemical_list: C463040:1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-(2-(mopholin-4-yl)ethyl)-1H-indole; D002186:Cannabinoids; D007211:Indoles; D009025:Morpholines; D043885:Receptor, Cannabinoid, CB2; D050916:TRPV Cation Channels; C494484:TRPV1 receptor