Cannabinoid activation of recombinant and endogenous vanilloid receptors

• Published in: European journal of pharmacology Vol. 424; no. 3; pp. 211 - 219
• Main Authors: Ralevic, Vera, Kendall, David A., Jerman, Jeffrey C., Middlemiss, Derek N., Smart, Darren
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 27.07.2001; Elsevier
• Subjects: Acetylcholine - pharmacology; Anandamide; Animals; Arachidonic Acids - pharmacology; Benzofurans - pharmacology; Biological and medical sciences; Bornanes - pharmacology; Calcitonin Gene-Related Peptide - pharmacology; Calcium - metabolism; Calcium Channel Blockers - pharmacology; Cannabinoid; Cannabinoids - pharmacology; Capsaicin; Capsaicin - analogs & derivatives; Capsaicin - pharmacology; Cardiovascular system; Cell Line; Dose-Response Relationship, Drug; Endocannabinoids; Humans; In Vitro Techniques; Medical sciences; Mesenteric arterial bed; Mesenteric Arteries - drug effects; Mesenteric Arteries - innervation; Mesenteric Arteries - physiology; Neurons, Afferent - physiology; Pharmacology. Drug treatments; Polyunsaturated Alkamides; Pyrazoles - pharmacology; Rats; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug - antagonists & inhibitors; Receptors, Drug - drug effects; Receptors, Drug - genetics; Receptors, Drug - physiology; Ruthenium - pharmacology; Sensory nerve; Synaptic Transmission - drug effects; Vanilloid receptor; Vasodilation - drug effects; Vasodilator Agents - pharmacology; Vasodilator agents. Cerebral vasodilators; Mesenteric arterial bed; Sensory nerve; Vanilloid receptor; Cannabinoid; Capsaicin; Anandamide; Human; Agonist; Vasodilator agent; Calcium; Rat; Rodentia; Smooth muscle; Ionic current; In vitro; Biological activity; Muscular relaxation; Vertebrata; Mesenteric artery; Mammalia; Animal; Blood vessel; Established cell line; Circulatory system; Recombinant protein; Biological receptor
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(01)01153-0

The effects of three structurally related cannabinoids on human and rat recombinant vanilloid VR1 receptors expressed in human embryonic kidney (HEK293) cells and at endogenous vanilloid receptors in the rat isolated mesenteric arterial bed were studied. In the recombinant cells, all three were full agonists, causing concentration-dependent increases in [Ca 2+] i (FLIPR™), with a rank order of potency relative to the vanilloids capsaicin and olvanil, of olvanil≥capsaicin>AM404 ((allZ)- N-(4-hydroxyphenyl)-5,8,11,14-eicosatetraenamide)>anandamide>methanandamide. These responses were inhibited by the vanilloid VR1 receptor antagonist, capsazepine. In the mesenteric arterial bed, vasorelaxation was evoked by these ligands with a similar order of potency. The AM404-induced vasorelaxation was virtually abolished by capsaicin pretreatment. AM404 inhibition of capsaicin-sensitive sensory neurotransmission was blocked by ruthenium red, but not by cannabinoid CB 1 and CB 2 receptor antagonists. AM404 had no effect on relaxations to calcitonin gene-related peptide. These data demonstrate that the vasorelaxant and sensory neuromodulator properties of AM404 in the rat isolated mesenteric arterial bed are mediated by vanilloid VR1 receptors.