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-type (CB1-R) and spleen-type (CB2-R) cannabinoid receptors in preimplantation embryo development using agonists and antagonists specific to CB1-R and CB2-R. The results establish that endogenous cannabinoid ligands, anandamide and sn-2 arachidonoylglycerol, arrest embryo development in vitro, and this effect is reversed by CB1-R antagonists SR141716A or AM 251, but not by SR144528, a CB2-R antagonist. A CB2-R selective agonist AM 663 failed to affect embryo development. These results suggest that cannabinoid effects on embryo development are mediated by CB1-R. We also observed that delta9-tetrahydrocannabinol ([-]THC) infused in the presence of cytochrome P450 inhibitors interfered with blastocyst implantation. This adverse effect was reversed by coinfusion of SR141716A. The less active stereoisomer (+)THC plus the inhibitors failed to affect implantation. Analysis of tissue levels demonstrated that uterine accumulation of (-)THC occurred when it was infused in the presence of the P450 inhibitors. These results demonstrate that the uterus and perhaps the embryo have the cytochrome P450 enzymes to metabolize (-)THC and neutralize its adverse effects on implantation. Collectively, the present study demonstrates that cannabinoid effects on embryo development and implantation are mediated by embryonic and/or uterine CB1-R, but not CB2-R.
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Department of Molecular and Integrative Physiology, Ralph L. Smith Research Center, University of Kansas Medical Center, Kansas City 66160-7338, USA.
Ma
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Andrenyak
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Schmid
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Schmid
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Moody
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Deng
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Makriyannis
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Dey
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D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D013759:Dronabinol / Q000494:pharmacology; D010064:Embryo Implantation / Q000187:drug effects*; D004622:Embryo, Mammalian / Q000187:drug effects; D047108:Embryonic Development; D005314:Embryonic and Fetal Development; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005989:Glycerides / Q000494:pharmacology; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011247:Pregnancy; D011720:Pyrazoles / Q000494:pharmacology; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000502:physiology*; D000077285:Rimonabant
D001095:Arachidonic Acids; D002186:Cannabinoids; D065607:Cytochrome P-450 Enzyme Inhibitors; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C103505:AM 251; D013759:Dronabinol; C094503:glyceryl 2-arachidonate; D000077285:Rimonabant; C078814:anandamide