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PNAS 103 (20): 7895-7900

Copyright © 2006 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / PHARMACOLOGY

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

Erica J. Carrier, John A. Auchampach, and Cecilia J. Hillard*

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226

Edited by Raphael Mechoulam, Hebrew University, Jerusalem, Israel, and accepted by the Editorial Board April 7, 2006

Received for publication December 28, 2005.

Abstract: The plant-derived cannabinoids {Delta}9-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 TNF{alpha} 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.

Key Words: adenosine • lipopolysaccharide • tetrahydrocannabinol • thymidine • tumor necrosis factor-{alpha}

Author contributions: C.J.H. designed research.; E.J.C. performed research; J.A.A. contributed new reagents/analytic tools; E.J.C. analyzed data; and E.J.C. wrote the paper.

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office. R.M. is a guest editor invited by the Editorial Board.

*To whom correspondence should be addressed at: Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226-0509. E-mail: chillard{at}mcw.edu

© 2006 by The National Academy of Sciences of the USA

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