TY - JOUR T1 - The Endocannabinoid 2-Arachidonylglycerol Decreases the Immunological Activation of Guinea Pig Mast Cells: Involvement of Nitric Oxide and Eicosanoids JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 256 LP - 264 DO - 10.1124/jpet.104.068635 VL - 311 IS - 1 AU - Alfredo Vannacci AU - Lucia Giannini AU - Maria Beatrice Passani AU - Annamaria Di Felice AU - Simone Pierpaoli AU - Giovanni Zagli AU - Ornella Fantappiè AU - Roberto Mazzanti AU - Emanuela Masini AU - Pier Francesco Mannaioni Y1 - 2004/10/01 UR - http://jpet.aspetjournals.org/content/311/1/256.abstract N2 - The antigen-induced release of histamine from sensitized guinea pig mast cells was dose-dependently reduced by endogenous (2-arachidonylglycerol; 2AG) and exogenous [(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol (CP55,940)] cannabinoids. The inhibitory action afforded by 2AG and CP55,940 was reversed by N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide (SR144528), a selective cannabinoid 2 (CB2) receptor antagonist, and left unchanged by the selective CB1 antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251). The inhibitory action of 2AG and CP55,940 was reduced by the unselective nitric-oxide synthase (NOS) inhibitor N-monomethyl-l-arginine methylester (l-NAME) and reinstated by l-arginine, the physiological substrate. The inhibitory action of 2AG and CP55,940 was also reduced by the unselective cyclooxygenase (COX) inhibitor indomethacin and the selective COX-2 blocker rofecoxib. Both 2AG and CP55,940 significantly increased the production of nitrite from mast cells, which was abrogated by l-NAME and N-(3-(aminomethyl)benzyl)acetamidine (1400W), a selective inducible NOS (iNOS) inhibitor. Nitrite production consistently paralleled a CP55,940-induced increase in the expression of iNOS protein in mast cells. Both 2AG and CP55,940 increased the generation of prostaglandin E2 from mast cells, which was abrogated by indomethacin and rofecoxib and parallel to the CP55,940-induced expression of COX-2 protein. Mast cell challenge with antigen was accompanied by a net increase in intracellular calcium levels. Both cannabinoid receptor ligands decreased the intracellular calcium levels, which were reversed by SR144528 and l-NAME. In unstimulated mast cells, both ligands increased cGMP levels. The increase was abrogated by SR144528, l-NAME, indomethacin, and rofecoxib. Our results suggest that 2AG and CP55,940 decreased mast cell activation in a manner that is susceptible to a CB2 receptor antagonist and to inhibition of nitric oxide and prostanoid pathways. The American Society for Pharmacology and Experimental Therapeutics ER -