EFFECTS OF CANNABINOIDS ON PREIMPLANTATION MOUSE EMBRYO DEVELOPMENT AND IMPLANTATION ARE MEDIATED BY BRAIN-TYPE CANNABINOID RECEPTORS

We examined the relative importance of G (Gi) protein-coupled brain-ty pe (CB1-R) and spleen-type (CB2-R) cannabinoid receptors in preimplant ation embryo development using agonists and antagonists specific to CB 1-R and CB2-R. The results establish that endogenous cannabinoid ligan ds, anandamide and sn-2 arachidonoylglycerol, arrest embryo developmen t in vitro, and this effect is reversed by CB1-R antagonists SR141716A or AM 251, but not by SR144528, a CBZ-R antagonist. A CB2-R selective agonist AM 663 failed to affect embryo development. These results sug gest that cannabinoid effects on embryo development are mediated by CB 1-R. We also observed that Delta(9)-tetrahydrocannabinol ([-]THC) infu sed in the presence of cytochrome P450 inhibitors interfered with blas tocyst implantation. This adverse effect was reversed by coinfusion of SR141716A. The less active stereoisomer (+)THC plus the inhibitors fa iled to affect implantation. Analysis of tissue levels demonstrated th at uterine accumulation of (-)THC occurred when it was infused in the presence of the P450 inhibitors. These results demonstrate that the ut erus and perhaps the embryo have the cytochrome P450 enzymes to metabo lize (-)THC and neutralize its adverse effects on implantation. Collec tively, the present study demonstrates that cannabinoid effects on emb ryo development and implantation are mediated by embryonic and/or uter ine CB1-R, but not CB2-R.