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

Abstract

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 (CB 2 ) receptor antagonist, and left unchanged by the selective CB 1 antagonistThe 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 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 E 2 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 CB 2 receptor antagonist and to inhibition of nitric oxide and prostanoid pathways.The immunosuppressive effect of tetrahydrocannabinol (THC) was formerly reported both in humans (Nahas et al., 1974) and experimental animals (Coffey et al., 1996). More recently, the effects of THC on human immune functions and host defense have been reviewed, providing evidence that THC can suppress the human immune response in a host of leukocyte subsets and alveolar macrophages, further stressing the relationship between marijuana smoking and immunologically-related diseases (Klein et al., 1998).Of the immunocompetent cells, mast cells are strategically placed in tissues that interface with the external environment and vary in the way in which their activation is modified by endocannabinoids. In the rat ear pin, the degranulation of resident mast cells induced by substance P is fully abrogated by the endogenous ligands at cannabinoid (CB) receptors arachidonylethanolamide (anandamide; AEA) and palmitoylethanol-

Anaphylaxis of small arteries: putative role of nitric oxide and prostanoids

“…Similar effects of indomethacin were obtained in dogs in vivo, where the anaphylactic coronary contraction was considerably diminished (39). These results may supplement the classical point of view that the main mediators of anaphylaxis eliciting the peak contraction to the antigen are histamine or/and serotonin (4,8). The interactions between their effects and the effects of cyclooxygenase products may be complicated, and unfortunately, there is almost no clear evidence of these interactions.…”

“…The main possible cause of hypotension is the release of mediators of anaphylaxis, following the IgE hypersensitivity reaction. Vasoactive substances such as histamine (1)(2)(3)(4), serotonin (5-7), and bradykinin (5,8) are well-recognized mediators of cardiac anaphylaxis. The antigenic stimulation of sensitized tissues is associated also with the release of slow-reacting substance of anaphylaxis (SRS-A), which mainly consists of systemic vasoconstrictors leukotrienes -LTD, LTC, and LTE (9, 10) -as well as thromboxane and endothelin (11).…”

Sensitization and Allergy to <i>Cannabis sativa</i> Leaves in a Population of Tomato <i>(Lycopersicon esculentum)</i>-Sensitized Patients

“…The pharmacologic (such as short-term bronchodilation) [21] and immunomodulatory effects [22, 23] of C. sativa -derived cannabinoids could favor the mildness of symptoms. In fact, 60% of the symptomatic patients were current smokers in spite of symptoms.…”

Cannabinoid receptor type 2 agonist JWH-133 deteriorates the liver toxicity induced by cypermethrin

“…However, application of CB1 and CB2 agonists and antagonists to rat peritoneal mast cells did not affect histamine release (62). In another study, 2-arachidonoylglycerol and CP55,940 decreased mast cell activation by being susceptible to a CB2 antagonist and inhibition of nitric oxide and prostanoid pathways (63). In the present study, CB2 expression was not observed in groups 1 and 4, but it was observed in groups treated with CYP.…”