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Research ArticleArticle

The Central Cannabinoid Receptor (CB1) Mediates Inhibition of Nitric Oxide Production by Rat Microglial Cells

Yaakov Waksman, John M. Olson, Steven J. Carlisle and Guy A. Cabral
Journal of Pharmacology and Experimental Therapeutics March 1999, 288 (3) 1357-1366;
Yaakov Waksman
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John M. Olson
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Steven J. Carlisle
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Guy A. Cabral
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Abstract

Upon activation, brain microglial cells release proinflammatory mediators, such as nitric oxide (NO), which may play an important role in the central nervous system antibacterial, antiviral, and antitumor activities. However, excessive release of NO has been postulated to elicit immune-mediated neurodegenerative inflammatory processes and to cause brain injury. In the present study, the effect of cannabinoids on the release of NO from endotoxin/cytokine-activated rat cortical microglial cells was evaluated. A drug dose-dependent (0.1 μM–8 μM) inhibition of NO release from rat microglial cells was exerted by the cannabinoid receptor high-affinity binding enantiomer (−)-CP55940. In contrast, a minimal inhibitory effect was exerted by the lower affinity binding paired enantiomer (+)-CP56667. Pretreatment of microglial cells with the Gαi/Gαo protein inactivator pertussis toxin, cyclic AMP reconstitution with the cell-permeable analog dibutyryl-cAMP, or treatment of cells with the Gαsactivator cholera toxin, resulted in reversal of the (−)-CP55940-mediated inhibition of NO release. A similar reversal in (−)-CP55940-mediated inhibition of NO release was effected when microglial cells were pretreated with the central cannabinoid receptor (CB1) selective antagonist SR141716A. Mutagenic reverse transcription-polymerase chain reaction, Western immunoblot assay using a CB1 receptor amine terminal domain-specific antibody, and cellular colocalization of CB1 and the microglial marker Griffonia simplicifolia isolectin B4 confirmed the expression of the CB1 receptor in rat microglial cells. Collectively, these results indicate a functional linkage between the CB1 receptor and cannabinoid-mediated inhibition of NO production by rat microglial cells.

Footnotes

  • Send reprint requests to: Dr. Guy A. Cabral, Department of Microbiology and Immunology, MCV Station, Box 980678, Virginia Commonwealth University, Richmond, VA 23298-0678. E-mail:gacabral{at}gems.vcu.edu

  • ↵1 This research was supported by National Institutes of Health awards: DA 05832, DA 05247, and DA 09158. Dr. Carlisle and John M. Olson were supported, in part, by T32DA07027 and T32AI07407, respectively.

  • Abbreviations:
    TNF-α
    tumor necrosis factor α
    IFN-γ
    γ-interferon
    LPS
    lipopolysaccharide
    Ast-CM
    astrocyte-conditioned medium
    CB1
    central cannabinoid receptor
    CNS
    central nervous system
    (−)-CP55940/(+)-CP56667
    −/+cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-trans-4-(3-hydroxypropyl)-cyclohexanol]
    FBS
    fetal bovine serum
    iNOS
    inducible nitric oxide synthase
    MRT-PCR
    mutagenic reverse transcription-polymerase chain reaction
    NO
    nitric oxide
    NBT
    nitroblue tetrazolium
    SR141716A
    (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-H-pyrazole-3-carboxamide hydrochloride
    GSA-I-B4
    Griffonia simplicifolia isolectin B4
    GFAP
    glial fibrillary acidic protein
    • Received May 28, 1998.
    • Accepted October 13, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 3
1 Mar 1999
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Research ArticleArticle

The Central Cannabinoid Receptor (CB1) Mediates Inhibition of Nitric Oxide Production by Rat Microglial Cells

Yaakov Waksman, John M. Olson, Steven J. Carlisle and Guy A. Cabral
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 1357-1366;

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Research ArticleArticle

The Central Cannabinoid Receptor (CB1) Mediates Inhibition of Nitric Oxide Production by Rat Microglial Cells

Yaakov Waksman, John M. Olson, Steven J. Carlisle and Guy A. Cabral
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 1357-1366;
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