Dual effect of cannabinoid CB1 receptor stimulation on a vanilloid VR1 receptor-mediated response

• Published in: Cellular and molecular life sciences : CMLS Vol. 60; no. 3; pp. 607 - 616
• Main Authors: Hermann, H, De Petrocellis, L, Bisogno, T, Schiano Moriello, A, Lutz, B, Di Marzo, V
• Format: Journal Article
• Language: English
• Published: Switzerland Springer Nature B.V 01.03.2003; Birkhäuser Verlag
• Subjects: Arachidonic Acids - pharmacology; Calcium - metabolism; Calcium Channel Blockers - pharmacology; Cannabinoids - pharmacology; Capsaicin - metabolism; Cellular biology; Cyclic AMP - metabolism; Dronabinol - analogs & derivatives; Dronabinol - pharmacology; Endocannabinoids; Humans; Kinases; Marijuana; Membranes; Molecular biology; Polyunsaturated Alkamides; Receptors, Cannabinoid; Receptors, Drug - agonists; Receptors, Drug - metabolism
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s000180300052

Cannabinoid CB1 receptors and vanilloid VR1 receptors are co-localized to some extent in sensory neurons of the spinal cord and dorsal root ganglia. In this study, we over-expressed both receptor types in human embryonic kidney (HEK)-293 cells and investigated the effect of the CB1 agonist HU-210 on the VR1-mediated increase in intracellular Ca2+ ([Ca2+]i), a well-known response of the prototypical VR1 agonist capsaicin. After a 5-min pre-treatment, HU-210 (0.1 microM) significantly enhanced the effect of several concentrations of capsaicin on [Ca2+]i in HEK-293 cells over-expressing both rat CB1 and human VR1 (CB1-VR1-HEK cells), but not in cells over-expressing only human VR1 (VR1-HEK cells). This effect was blocked by the CB1 receptor antagonist SR141716A (0.5 microM), and by phosphoinositide-3-kinase and phospholipase C inhibitors. The endogenous agonist of CB1 and VR1 receptors, anandamide, was more efficacious in inducing a VR1-mediated stimulation of [Ca2+]i in CB1-VR1-HEK cells than in VR1-HEK cells, and part of its effect on the former cells was blocked by SR141716A (0.5 microM). Pre-treatment of CB1-VR1-HEK cells with forskolin, an adenylate cyclase activator, enhanced the capsaicin effect on [Ca2+]i. HU-210, which in the same cells inhibits forskolin-induced enhancement of cAMP levels, blocked the stimulatory effect of forskolin on capsaicin. Our data suggest that in cells co-expressing both CB1 and VR1 receptors, pre-treatment with CB1 agonists inhibits or stimulates VR1 gating by capsaicin depending on whether or not cAMP-mediated signalling has been concomitantly activated.