title: Cannabinoid-mediated antinociception is enhanced in rat osteoarthritic knees.
abstract: OBJECTIVE
  To determine whether local administration of the cannabinoid 1 (CB(1)) receptor agonist arachidonyl-2-chloroethylamide (ACEA) can modulate joint nociception in control rat knee joints and in experimental osteoarthritis (OA).
  
  
  METHODS
  OA was induced in male Wistar rats by intraarticular injection of 3 mg of sodium mono-iodoacetate, with a recovery period of 14 days. Electrophysiologic recordings were made of knee joint primary afferent nerve fibers in response to normal rotation and noxious hyperrotation of the joint both before and after close intraarterial injection of different doses of ACEA.
  
  
  RESULTS
  Local application of the CB(1) agonist significantly reduced the firing rate of afferent nerve fibers by up to 50% in control knee joints (n=19) and up to 62% in OA knee joints (n=29; P<0.01). Coadministration of the CB(1) receptor antagonist AM251 or the transient receptor potential vanilloid 1 (TRPV-1) ion channel antagonist SB366791 significantly reduced the desensitizing effect of ACEA. The CB(1) receptor antagonist AM251 by itself had no effect in the control joint but significantly increased the firing rate of afferent nerve fibers in the OA joint.
  
  
  CONCLUSIONS
  These findings indicate that activation of peripheral CB(1) receptors reduces the mechanosensitivity of afferent nerve fibers in control and OA knee joints. Blockade of either the CB(1) receptor or the TRPV-1 channel significantly reduced the efficacy of ACEA, which suggests that both receptors are involved in cannabinoid-mediated antinociception. The increased nerve activity observed following CB(1) receptor antagonism suggests a tonic release of endocannabinoids during OA. As such, peripheral CB(1) receptors may be important targets in controlling OA pain.
authors.affiliation: University of Calgary, Calgary, Alberta, Canada.
authors.forename: Niklas
authors.initials: N
authors.lastname: Schuelert
authors.forename: Jason J
authors.initials: JJ
authors.lastname: McDougall
mesh_terms: D000344:Afferent Pathways / Q000187:drug effects; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D002934:Cinnamates / Q000494:pharmacology; D007719:Knee Joint / Q000294:innervation; D008297:Male; D009619:Nociceptors / Q000187:drug effects*; D020370:Osteoarthritis, Knee / Q000150:complications*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors
chemical_list: D000813:Anilides; D001095:Arachidonic Acids; D002934:Cinnamates; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C119325:arachidonyl-2-chloroethylamide; C103505:AM 251