The cannabinomimetic arachidonyl‐2‐chloroethylamide (ACEA) acts on capsaicin‐sensitive TRPV1 receptors but not cannabinoid receptors in rat joints

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Abstract
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 CB1 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 CB2 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 (TRPV1) 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 (Pvia TRPV1 receptors located on the terminal branches of capsaicin‐sensitive afferent nerves innervating the joint. British Journal of Pharmacology (2004) 142, 1361–1367. doi:10.1038/sj.bjp.0705902