title: Cannabidiol, unlike synthetic cannabinoids, triggers activation of RBL-2H3 mast cells.
abstract: Cannabidiol (CBD), a prominent psychoinactive component of cannabis with negligible affinity for known cannabinoid receptors, exerts numerous pharmacological actions, including anti-inflammatory and immunosuppressive effects, the underlying mechanisms of which remain unclear. In the current study, we questioned whether CBD modulates activation of mast cells, key players in inflammation. By using the rat basophilic leukemia mast cell line (RBL-2H3), we demonstrate that CBD (3-10 muM) augments beta-hexosaminidase release, a marker of cell activation, from antigen-stimulated and unstimulated cells via a mechanism, which is not mediated by G(i)/G(o) protein-coupled receptors but rather is associated with a robust rise in intracellular calcium ([Ca(2+)](i)) levels sensitive to clotrimazole and nitrendipine (10-30 muM). This action, although mimicked by Delta(9)-tetrahydrocannabinol (THC), is opposite to that inhibitory, exerted by the synthetic cannabinoids WIN 55,212-2 and CP 55,940. Moreover, the vanilloid capsaicin, a full agonist of transient receptor potential channel VR1, did not affect [Ca(2+)](i)levels in the RBL-2H3 cells, thus excluding the involvement of this receptor in the CBD-mediated effects. Together, these results support existence of yet-to-be identified sites of interaction, i.e., receptors and/or ion channels associated with Ca(2+) influx of natural cannabinoids such as CBD and THC, the identification of which has the potential to provide for novel strategies and agents of therapeutic interest.
authors.affiliation: Research and Innovation (R&I) Company, Padova, Italy.
authors.forename: Elda Del
authors.initials: ED
authors.lastname: Giudice
authors.forename: Luciano
authors.initials: L
authors.lastname: Rinaldi
authors.forename: Marzia
authors.initials: M
authors.lastname: Passarotto
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Facchinetti
authors.forename: Antonello
authors.initials: A
authors.lastname: D'Arrigo
authors.forename: Adriano
authors.initials: A
authors.lastname: Guiotto
authors.forename: Maurizio Dalle
authors.initials: MD
authors.lastname: Carbonare
authors.forename: Leontino
authors.initials: L
authors.lastname: Battistin
authors.forename: Alberta
authors.initials: A
authors.lastname: Leon
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002185:Cannabidiol / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D015550:Cell Degranulation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D003511:Cyclohexanols / Q000494:pharmacology; D013759:Dronabinol / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D051381:Rats; D050916:TRPV Cation Channels / Q000819:agonists; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism*
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D003511:Cyclohexanols; D009025:Morpholines; D009281:Naphthalenes; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; 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; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D001619:beta-N-Acetylhexosaminidases; D002211:Capsaicin; D002118:Calcium