Paria B C, Ma W, Andrenyak D M, Schmid P C, Schmid H H, Moody D E, Deng H, Makriyannis A, Dey S K
Department of Molecular and Integrative Physiology, Ralph L. Smith Research Center, University of Kansas Medical Center, Kansas City 66160-7338, USA.
Biol Reprod. 1998 Jun;58(6):1490-5. doi: 10.1095/biolreprod58.6.1490.
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.
我们使用CB1-R和CB2-R特异性激动剂和拮抗剂，研究了G（Gi）蛋白偶联的脑型（CB1-R）和脾型（CB2-R）大麻素受体在植入前胚胎发育中的相对重要性。结果表明，内源性大麻素配体花生四烯乙醇胺和sn-2花生四烯酸甘油酯在体外会阻止胚胎发育，CB1-R拮抗剂SR141716A或AM 251可逆转这种作用，但CB2-R拮抗剂SR144528则不能。CB2-R选择性激动剂AM 663对胚胎发育没有影响。这些结果表明，大麻素对胚胎发育的影响是由CB1-R介导的。我们还观察到，在细胞色素P450抑制剂存在的情况下注入的Δ9-四氢大麻酚（[-]THC）会干扰胚泡着床。SR141716A共同注入可逆转这种不利影响。活性较低的立体异构体（+）THC与抑制剂一起未能影响着床。组织水平分析表明，在P450抑制剂存在的情况下注入（-）THC时，子宫会出现（-）THC的蓄积。这些结果表明，子宫以及可能胚胎具有细胞色素P450酶来代谢（-）THC并中和其对着床的不利影响。总体而言，本研究表明，大麻素对胚胎发育和着床的影响是由胚胎和/或子宫CB1-R介导的，而非CB2-R。
