Cannabinoid activation of recombinant and endogenous vanilloid receptors

The effects of three structurally related cannabinoids on human and rat rec ombinant vanilloid VR1 receptors expressed in human embryonic kidney (HEK29 3) cells and at endogenous vanilloid receptors in the rat isolated mesenter ic arterial bed were studied. In the recombinant cells, all three were full agonists, causing concentration-dependent increases in [Ca2+](i) (FLIPR(TM )), with a rank order of potency relative to the vanilloids capsaicin and o lvanii, of olvanil greater than or equal to capsaicin > AM404 ((allZ)-N-(4- hydroxyphenyl)-5,8,11,14-eicosatetraenamide) > anandamide > methanandamide. These responses were inhibited by the vanilloid VR1 receptor antagonist, c apsazepine. In the mesenteric arterial bed, vasorelaxation was evoked by th ese ligands with a similar order of potency. The AM404-induced vasorelaxati on was virtually abolished by capsaicin pretreatment. AM404 inhibition of c apsaicin-sensitive sensory neurotransmission was blocked by ruthenium red, but not by cannabinoid CB1 and CB2 receptor antagonists. AM404 had no effec t on relaxations to calcitonin gene-related peptide. These data demonstrate that the vasorelaxant and sensory neuromodulator properties of AM404 in th e rat isolated mesenteric arterial bed are mediated by vanilloid VR1 recept ors. (C) 2001 Elsevier Science B.V. All rights reserved.