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INFLAMMATION AND IMMUNOPHARMACOLOGY

The Endocannabinoid 2-Arachidonylglycerol Decreases the Immunological Activation of Guinea Pig Mast Cells: Involvement of Nitric Oxide and Eicosanoids

Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy

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.

Address correspondence to: Dr. Pier Francesco Mannaioni, Department of Preclinical and Clinical Pharmacology, University of Florence, Viale G. Pier-accini, n 6, 50139 Florence, Italy. E-mail: pierfrancesco.mannaioni{at}unifi.it

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