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Vol. 293, Issue 1, 136-150, April 2000
Department of Immunology Schering-Plough Research Institute,
Kenilworth, New Jersey
Previous studies have shown that mice primed with
Corynebacterium parvum produce higher levels of
inflammatory cytokines than unprimed mice upon challenge with
lipopolysaccharide (LPS). Herein, we describe experiments in which 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-
8
tetrahydrocannabinol-dimethylheptyl], were examined for their effects
on LPS-induced cytokines in C. parvum-primed and
unprimed mice. These agonists have been reported to bind
selectively to the CB2 and CB1 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 necrosis factor-
and interleukin-12 (IL-12)
and increased IL-10 when administered to mice before LPS. The drugs
also protected C. parvum mice (but not unprimed mice)
against the lethal effects of LPS. The protection afforded 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-methyl-1H-pyrazole-3-carboxamide hydrochloride], a selective CB1 receptor antagonist, but not by SR144528
{N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]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 itself modulated cytokine responses in a manner identical with that of WIN 55212-2 and HU-210 when administered alone to mice.
The agonist-like effects of SR141716A, which were more striking in
unprimed than in primed mice, suggested that the antagonist also could
function as a partial agonist at the CB1 receptor. Our findings
indicate a role for the CB1 receptor subtype in cytokine modulation by
CB ligands.
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