The cannabinomimetic arachidonyl-2-chloroethylamide (ACEA) acts on capsaicin-sensitive TRPV1 receptors but not cannabinoid receptors in rat joints.
The vasoactive effects of the synthetic cannabinoid (CB) arachidonyl-2-chloroethylamide (ACEA) was tested in the knee joints of urethane-anaesthetised rats. Experiments were also performed to determine whether these vasomotor responses could be blocked by the selective CB(1) receptor antagonists AM251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) (10(-9) mol) and AM281 (1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide) (10(-8) mol), as well as the selective CB(2) receptor antagonist AM630 (6-iodo-2-methyl-1-[2-4(morpholinyl)ethyl]-[1H-indol-3-yl](4-methoxyphenyl)methanone) (10(-8) mol). Peripheral application of ACEA (10(-14)-10(-9) mol) onto the exposed surface of the knee joint capsule caused a dose-dependent increase in synovial blood flow. The dilator action of the CB occurred within 1 min after drug administration and rapidly returned to control levels shortly thereafter. The maximal vasodilator effect of ACEA corresponded to a 30% increase in articular perfusion compared to control levels. The hyperaemic action of ACEA was not significantly altered by coadministration of AM251, AM281 or AM630 (P>0.05; two-way ANOVA). The transient receptor potential channel vanilloid receptor 1 (TRPV(1)) antagonist capsazepine (10(-6) mol) significantly reduced the vasodilator effect of ACEA on joint blood vessels (P=0.002). Furthermore, destruction of unmyelinated and thinly myelinated joint sensory nerves by capsaicin (8-methyl-N-vanillyl-6-nonenamide) treatment also attenuated ACEA responses (P<0.0005). These data clearly demonstrate a vasodilator effect of the cannabinomimetic ACEA on knee joint perfusion. Rather than a classic CB receptor pathway, ACEA exerts its vasomotor influence by acting via TRPV(1) receptors located on the terminal branches of capsaicin-sensitive afferent nerves innervating the joint.
Department of Physiology and Biophysics, 3300, Hospital Drive NW, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
Chris L
CL
Baker
Jason J
JJ
McDougall
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D002186:Cannabinoids / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007473:Ion Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D007719:Knee Joint / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid / Q000502:physiology*; D050916:TRPV Cation Channels
D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D002186:Cannabinoids; D007473:Ion Channels; D043882:Receptors, Cannabinoid; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C119325:arachidonyl-2-chloroethylamide; D002211:Capsaicin