Effects of cannabinoid receptor agonist and antagonist ligands on production of inflammatory cytokines and anti-inflammatory interleukin-10 in endotoxemic mice

Previous studies have shown that mice primed with Corynebacterium parvum pr oduce higher levels of inflammatory cytokines than unprimed mice upon chall enge with lipopolysaccharide (LPS). Herein, we describe experiments in whic h two cannabinoid (CB) agonists, WIN 55212-2 {(R)-(+)-[2,3-dihydro-5-methyl -3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]1,4-benzoxazin-6-yl](1-naphthyl) methanone} and HU-210 [(-)-11-hydroxy-Delta 8 tetrahydrocannabinol-dimethyl heptyl], were examined for their effects on LPS-induced cytokines in C. par vum-primed and unprimed mice. These agonists have been reported to bind sel ectively to the CB2 and CBI receptor subtypes, respectively. WIN 55212-2 (3 .1-50 mg/kg i.p.) and HU-210 [(0.05-0.4 mg/kg i.p.) decreased serum tumor n ecrosis factor-alpha and interleukin-12 (IL-12) and increased IL-10 when ad ministered to mice before LPS. The drugs also protected C. parvum mice (but not unprimed mice) against the lethal effects of LPS. The protection affor ded to C. parvum mice could not be attributed to the higher levels of IL-10 present in these mice after agonist treatment. The WIN 55212-2- and HU-210 -mediated changes in the responsiveness of mice to LPS were antagonized by SR141716A [N-(piperdin -1-yl)-5-(4-chloropheny)-1- (2,4-dichloropheny)-4-me thyl-1H-pyrazole-3-carboxamide hydrochloride], a selective CB1 receptor ant agonist, but not by SR144528 {N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]hep tan-2-y]5-(4-choro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3 carboxamide }, a selective antagonist at the CB2 receptor. Therefore, both CB agonists modulated LPS responses through the CB1 receptor. Surprisingly, SR141716A i tself modulated cytokine responses in a manner identical with that of WIN 5 5212-2 and HU-210 when administered atone to mice. The agonist-like effects of SR141716A, which were more striking in unprimed than in primed mice, su ggested that the antagonist also could function as a partial agonist at the CBI receptor. Our findings indicate a role for the CB1 receptor subtype in cytokine modulation by CB ligands.