Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB2 receptor

Cannabinoids have immunomodulatory as well as psychoactive effects, Because the central cannabinoid receptor (cannabinoid CB2 receptor) is highly expr essed in many neuronal tissues and the peripheral cannabinoid receptor (can nabinoid CB2 receptor) is highly expressed in immune cells, it has been sug gested that the central nervous system effects of cannabinoids are mediated by cannabinoid CB2 receptors and that the immune effects are mediated by c annabinoid CB2 receptors. To test this hypothesis, we have generated the fi rst mouse strain with a targeted mutation in the cannabinoid CB2 receptor g ene. Binding studies using the highly specific synthetic cannabinoid recept or agonist (-)-cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hy droxypropyl)cyclohexanol ([H-3]CP 55,940) revealed no residual cannabinoid binding sites in the spleen of the cannabinoid CB2 receptor knockout mice, while binding in the central nervous system was unchanged. Cannabinoid CB2 receptor knockout mice, which appear healthy, are fertile and care for thei r offspring. Fluorescence activated cell sorting (FACS) analysis showed no differences in immune cell populations between cannabinoid CB2 receptor kno ckout and wildtype mice. We investigated the immunomodulatory effects of ca nnabinoids in cannabinoid CB2 receptor deficient mice using a T cell co-sti mulation assay. Delta(9)Tetrahydrocannabinol inhibits helper T cell activat ion through macrophages derived from wild type, but not from knockout mice, thus indicating that this effect is mediated by the cannabinoid CB2 recept or. In contrast, central nervous system effects of cannabinoids were not al tered in these mice. Our results suggest that cannabinoid CB2 receptor-spec ific ligands may be clinically useful in the modulation of macrophage immun e function while exhibiting no central nervous system activity. Furthermore , we conclude that the cannabinoid CB2 receptor knockout mouse is a useful animal model in which to study the role of the cannabinoid system in immuno regulation. (C) 2000 Elsevier Science B.V. All rights reserved.