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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Effects of Cannabinoid Receptor Agonist and Antagonist Ligands on Production of Inflammatory Cytokines and Anti-Inflammatory Interleukin-10 in Endotoxemic Mice

Sidney R. Smith, Carol Terminelli and Georgetta Denhardt
Journal of Pharmacology and Experimental Therapeutics April 2000, 293 (1) 136-150;
Sidney R. Smith
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Carol Terminelli
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Georgetta Denhardt
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Abstract

Previous studies have shown that mice primed withCorynebacterium 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-Δ8tetrahydrocannabinol-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-α 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.

Footnotes

  • Send reprint requests to: Sidney R. Smith, Department of Immunology, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033. E-mail: sidney.smith{at}spcorp.com

  • Abbreviations:
    CB
    cannabinoid
    THC
    tetrahydrocannabinol
    CP 55940
    {(−)-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]4-[3-hydroxypropyl]cyclohexan-1-ol}
    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
    SR141716A
    N-(piperdin-1-yl)-5-(4-chloropheny)-1-(2,4-dichloropheny)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride
    CNS
    central nervous system
    GPCR
    G protein-coupled receptor
    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
    LPS
    lipopolysaccharide
    HU-210
    (−)-11-hydroxy-Δ8tetrahydrocannabinol-dimethylheptyl
    TNF-α
    tumor necrosis factor-α
    IL
    interleukin
    HU-211
    [(+)-(3S,4S)-7-hydroxy Δ6-tetrahydrocannabinol-1,1-dimethylheptyl]
    • Received October 5, 1999.
    • Accepted December 10, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 293 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 1
1 Apr 2000
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Effects of Cannabinoid Receptor Agonist and Antagonist Ligands on Production of Inflammatory Cytokines and Anti-Inflammatory Interleukin-10 in Endotoxemic Mice

Sidney R. Smith, Carol Terminelli and Georgetta Denhardt
Journal of Pharmacology and Experimental Therapeutics April 1, 2000, 293 (1) 136-150;

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Effects of Cannabinoid Receptor Agonist and Antagonist Ligands on Production of Inflammatory Cytokines and Anti-Inflammatory Interleukin-10 in Endotoxemic Mice

Sidney R. Smith, Carol Terminelli and Georgetta Denhardt
Journal of Pharmacology and Experimental Therapeutics April 1, 2000, 293 (1) 136-150;
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  • Cannabinoid-Mediated Elevation of Intracellular Calcium: A Structure-Activity Relationship
  • Protease-Activated Receptor-2 Peptides Activate Neurokinin-1 Receptors in the Mouse Isolated Trachea
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