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Effects of cannabinoids on preimplantation mouse embryo development and implantation are mediated by brain-type
B C Paria1, W Ma, D M Andrenyak
1Department of Molecular and Integrative Physiology, Ralph L. Smith Research Center, University of Kansas Medical Center, Kansas City 66160-7338, USA.
Abstract:
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.
Insights
Endogenous cannabinoids arrest embryo development, but CB1-R antagonists reverse this effect. Cannabinoid exposure also impairs implantation, mediated by CB1-R in the uterus and embryo.
Area of Science:
- Reproductive biology
- Endocrinology
- Pharmacology
Background:
- Cannabinoid receptors, CB1-R and CB2-R, are G (Gi) protein-coupled receptors.
- Endocannabinoids like anandamide and sn-2 arachidonoylglycerol play roles in reproductive processes.
- The specific roles of CB1-R and CB2-R in early embryonic development and implantation are not fully understood.
Purpose of the Study:
- To investigate the relative importance of CB1-R and CB2-R in preimplantation embryo development and blastocyst implantation.
- To determine the role of endogenous cannabinoid ligands and delta9-tetrahydrocannabinol (THC) in these processes.
Main Methods:
- Utilized specific agonists and antagonists for CB1-R and CB2-R to study their effects on embryo development in vitro.
- Assessed the impact of delta9-tetrahydrocannabinol (THC) and its stereoisomers on blastocyst implantation in the presence of cytochrome P450 inhibitors.
- Analyzed tissue levels of THC to understand its metabolic fate and uterine accumulation.
Main Results:
- Endogenous cannabinoids (anandamide, sn-2 arachidonoylglycerol) arrested embryo development in vitro, an effect reversed by CB1-R antagonists but not CB2-R antagonists.
- A CB2-R selective agonist did not affect embryo development, suggesting CB1-R mediates cannabinoid effects on development.
- Delta9-THC interfered with blastocyst implantation, an effect reversed by a CB1-R antagonist, and this was linked to uterine accumulation of THC, indicating metabolism by uterine and possibly embryonic cytochrome P450 enzymes.
Conclusions:
- Cannabinoid-induced effects on preimplantation embryo development and blastocyst implantation are primarily mediated by the CB1-R.
- CB2-R does not appear to play a significant role in these early reproductive events.
- The uterus and potentially the embryo possess the enzymatic machinery (cytochrome P450) to metabolize THC, mitigating its adverse effects on implantation.