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.

Cannabinoids, Endocannabinoids, and Related Analogs in Inflammation

“…Although CBD did not reduce inducible nitric oxide synthase (iNOS) in these studies, others (14,15) have reported that CBD does inhibit iNOS in a beta-amyloidinduced murine model of neuroinflammation. In contrast to these receptor studies, increased activation of rat mast cells by CBD was not mimicked by a full agonist of vanilloid receptor type 1 (16). In addition, CBD is an antagonist of CB receptor agonists in mouse brain and in membranes from cells transfected with human CB2 receptors (17).…”

Effect of Chlorogenic acid on mast cell-dependent anaphylactic reaction

“…Thus, compound 48/80 has been used as a direct and convenient agent for the study of unknown compounds on mast cell-dependent anaphylactic reaction. Additionally, the rat basophilic leukemia cell line RBL-2H3, displaying characteristics of mucosal-type mast cells, is considered as a good model for studying the comprehensive events on mast cell activation [17][18][19].…”

Cannabinoids and the immune system: An overview

“…MC are found in nervous system, mucosal and connective tissue, and are involved in allergic and inflammatory responses. Despite controversy on CBR expression and cannabinoid effects on MC (Croxford and Yamamura, 2005), it is accepted that CB2R can be expressed by MC, although PEA can control MC degranulation via a CB1R/CB2R-independent mechanism (Giudice et al, 2007;De Filippis et al, 2008). Cannabinoid ligands, including PEA and related compounds, may act to control mast cell activation and degranulation early during the inflammatory response (De Filippis et al, 2008).…”