Cited by 498Cannabis and Cannabinoid ResearchAdenosine and Purinergic SignalingInflammatory mediators and NSAID effects

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Inhibition of an equilibrative nucleoside transporter by cannabidiol: A mechanism of cannabinoid immunosuppression

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Carrier, Erica J., Auchampach, John A., Hillard, Cecilia J.·2006·Proceedings of the National Academy of Sciences

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Abstract

The plant-derived cannabinoids delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) both have immunosuppressive effects; although some effects of THC are mediated by the CB2 receptor, CB2 binds CBD weakly. In examining the effects of THC and CBD on microglial proliferation, we found that these compounds potently inhibit [3H]thymidine incorporation into a murine microglial cell line with no effect on cell cycle. Treatment with THC and CBD decreased [3H]thymidine uptake into microglia, with IC50 values that match inhibition of [3H]thymidine incorporation into DNA. CBD and, less potently, THC decreased uptake of [3H]adenosine to a similar extent as [3H]thymidine in both murine microglia and RAW264.7 macrophages. Binding studies confirm that CBD binds to the equilibrative nucleoside transporter 1 with a Ki < 250 nM. Because adenosine agonists have antiinflammatory effects, and because uptake of adenosine is a primary mechanism of terminating adenosine signaling, we tested the hypothesis that CBD is immunosuppressive because it enhances endogenous adenosine signaling. In vivo treatment with a low dose of CBD decreases TNFalpha production in lipopolysaccharide-treated mice; this effect is reversed with an A2A adenosine receptor antagonist and abolished in A2A receptor knockout mice. These studies demonstrate that CBD has the ability to enhance adenosine signaling through inhibition of uptake and provide a non-cannabinoid receptor mechanism by which CBD can decrease inflammation.

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Authors: Carrier, E. J., Auchampach, J. A., & Hillard, C. J.
Affiliations: Medical College of Wisconsin (US)
ORCID: Carrier, Erica J.
Auchampach, John A.
Hillard, Cecilia J.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2006-05-16
Volume: 103
Issue: 20
Pages: 7895-7900
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0511232103
OpenAlex: W2067960394
Cited by: 497
References: 39
Citations by year: 2026: 20 · 2025: 30 · 2024: 29 · 2023: 33 · 2022: 40 · 2021: 33 · 2020: 40 · 2019: 32 · 2018: 19 · 2017: 25 · 2016: 20 · 2015: 19 · 2014: 11 · 2013: 20 · 2012: 24
FWCI: 14.00
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Heart, Lung, and Blood Institute (HL 077707, R01HL077707)
National Institute on Drug Abuse (R01DA009155, DA 16967, DA09155, R01DA016967)
National Institute of Neurological Disorders and Stroke (NS041314, R01NS041314)
Topics: Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
Health Sciences › Medicine › Pharmacology (medical) › Inflammatory mediators and NSAID effects
Keywords: cannabidiol, delta-9-tetrahydrocannabinol, equilibrative nucleoside transporter 1, adenosine uptake, adenosine signaling, adenosine A2A receptor, microglial proliferation, macrophages, TNF-α, lipopolysaccharide-induced inflammation, anti-inflammatory activity
MeSH terms: Rimonabant, Adenosine, Animals, Camphanes, Cannabidiol, Cell Line, DNA, Immunosuppression Therapy, Lipopolysaccharides, Male, Mice, Inbred C57BL, Piperidines, Psychotropic Drugs, Pyrazoles, Dronabinol, Thymidine, Tumor Necrosis Factor-alpha, Microglia, Nucleoside Transport Proteins, Equilibrative Nucleoside Transporter 1, Cell Proliferation, Mice

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Inhibition of an equilibrative nucleoside transporter by cannabidiol: A mechanism of cannabinoid immunosuppression

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