TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons.
Transient receptor potential V2 (TRPV2) has been proposed to be a high-threshold thermosensor. However, further elucidation of the channel properties and physiological role of TRPV2 have been hindered by the lack of selective pharmacological tools as well as by the species-dependent differences in the activation of this channel. In the present study, we have used cell-based calcium mobilization and electrophysiological assays to identify and characterize several novel cannabinoid TRPV2 agonists. Among these, cannabidiol was found to be the most robust and potent (EC(50) = 3.7 microM), followed by Delta(9)-tetrahydrocannabinol (EC(50) = 14 microM) and cannabinol (EC(50) = 77.7 microM). We also demonstrated that cannabidiol evoked a concentration-dependent release of calcitonin gene-related peptide (CGRP) from cultured rat dorsal root ganglion neurons in a cannabinoid receptor- and TRPV1-independent manner. Moreover, the cannabidiol-evoked CGRP release depended on extracellular calcium and was blocked by the nonselective TRP channel blocker, ruthenium red. We further provide evidence through the use of small interfering RNA knockdown and repetitive stimulation studies, to show that cannabidiol-evoked CGRP release is mediated, at least in part, by TRPV2. Together, these data suggest not only that TRPV2 may comprise a mechanism whereby cannabidiol exerts its clinically beneficial effects in vivo, but also that TRPV2 may constitute a viable, new drug target.
Qin
Ning
N
Analgesics Team, East Coast Research and Early Development, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477-0776, USA.
Neeper
Michael P
MP
Liu
Yi
Y
Hutchinson
Tasha L
TL
Lubin
Mary Lou
ML
Flores
Christopher M
CM
D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002185:Cannabidiol / Q000494:pharmacology*; D002478:Cells, Cultured; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D011863:Radioimmunoassay / Q000379:methods; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D050916:TRPV Cation Channels / Q000378:metabolism*
D048588:Benzoxazines; D004791:Enzyme Inhibitors; D009025:Morpholines; D009281:Naphthalenes; D034741:RNA, Small Interfering; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C476722:Trpv2 protein, rat; D002185:Cannabidiol; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium