PHARMACOLOGY Cannabinoids Inhibit Nucleoside Transporter to Mediate Immunosuppression

Cannabidiol (CBD) is a plant-derived cannabinoid with immunosuppressive effects, yet CBD does not bind to the CB₂ cannabinoid receptor with high affinity. Carrier et al. report that CBD and ⁹-tetrahydrocannabinol (THC) decreased thymidine and adenosine uptake into a microglia cell line and a macrophage cell line by inhibiting the nucleoside transporter, which transports both thymidine and adenosine. CBD competitively inhibited binding of the drug S-(4-nitrobenzyl)-6-thioinosine (NBMPR), which is an inhibitor of the equilibrative nucleoside transporter (ENT). ENT1 was the primary nucleoside transporter in the macrophage cell line tested. Adenosine is an endogenous immunosuppressive agent that binds to plasma membrane adenosine receptors, and adenosine signaling is terminated by uptake. Thus, inhibition of the ENT should enhance the immunosuppressive signal mediated by adenosine. Administration of CBD decreased the production of tumor necrosis factor-α (TNF-α) in mice exposed to lipopolysaccharide (LPS). If an inhibitor of the adenosine A_2A receptor was also given, then CBD was ineffective at decreasing TNF-α production in the LPS-treated mice. Thus, ENT is a target for cannabinoids, and those cannabinoids that exhibit high affinity for ENT and low affinity for the CB receptors may provide selective immunosuppressive benefits without the cognitive effects and "high" associated with those with high affinity for CB receptors.

E. J. Carrier, J. A. Auchampach, C. J. Hillard, Inhibition of an equilibrative nucleoside transporter by cannabidiol: A mechanism of cannabinoid immunosuppression. Proc. Natl. Acad. Sci. U.S.A. 103, 7895-7900 (2006). [Abstract] [Full Text]