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Inhibition of an equilibrative nucleoside transporter by cannabidiol: A mechanism of cannabinoid immunosuppression
Open accessAbstract
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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“facilitation of adenosine signaling produces anxiolytic-like effects (Carrier et al., 2006).”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Carrier et al., 2006
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“CBD is an inhibitor of adenosine uptake and facilitation of adenosine signaling produces anxiolytic-like effects (Carrier et al., 2006).”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Carrier et al., 2006
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Cited by
Sorted by citations
The Endocannabinoid System as an Emerging Target of Pharmacotherapy
Pacher, P., Bátkai, S., & Kunos, G. (2006) · Pharmacological Reviews · doi:10.1124/pr.58.3.2 · Cited by 2,077
Pertwee, R. G. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707442 · Cited by 2,047
Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.
Russo, E. B. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01238.x · Cited by 1,535
The endocannabinoid system and the brain.
Mechoulam, R., & Parker, L. A. (2013) · Annual Review of Psychology · doi:10.1146/annurev-psych-113011-143739 · Cited by 1,090
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Metadata
- Authors
- Carrier, E. J., Auchampach, J. A., & Hillard, C. J.
- Affiliations
- Medical College of Wisconsin (US)
- 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
- 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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