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Proceedings of the National Academy of Sciences, Vol 92, 9460-9464, Copyright © 1995 by National Academy of Sciences
BC Paria, SK Das and SK Dey
Using a reverse transcription-coupled PCR, we demonstrated that both brain
and spleen type cannabinoid receptor (CB1-R and CB2-R, respectively) mRNAs
are expressed in the preimplantation mouse embryo. The CB1-R mRNA
expression was coincident with the activation of the embryonic genome late
in the two-cell stage, whereas the CB2-R mRNA was present from the one-cell
through the blastocyst stages. The major psychoactive component of
marijuana (-)-
ARTICLE
The Preimplantation Mouse Embryo is a Target for Cannabinoid Ligand-Receptor Signaling
-tetrahydrocannabinol [(-)-THC] inhibited forskolin-stimulated
cAMP generation in the blastocyst, and this inhibition was prevented by
pertussis toxin. However, the inactive cannabinoid cannabidiol (CBD) failed
to influence this response. These results suggest that cannabinoid
receptors in the embryo are coupled to inhibitory guanine nucleotide
binding proteins. Further, the oviduct and uterus exhibited the enzymatic
capacity to synthesize the putative endogenous cannabinoid ligand
arachidonylethanolamide (anandamide). Synthetic and natural cannabinoid
agonists [WIN 55,212-2, CP 55,940, (-)-THC, and anandamide], but not CBD or
arachidonic acid, arrested the development of two-cell embryos primarily
between the four-cell and eight-cell stages in vitro in a dose-dependent
manner. Anandamide also interfered with the development of eight-cell
embryos to blastocysts in culture. The autoradiographic studies readily
detected binding of [3H]anandamide in embryos at all stages of
development. Positive signals were present in one-cell embryos and all
blastomeres of two-cell through four-cell embryos. However, most of the
binding sites in eight-cell embryos and morulae were present in the outer
cells. In the blastocyst, these signals were primarily localized in the
mural trophectoderm with low levels of signals in the polar trophectoderm,
while little or no signals were noted in inner cell mass cells. These
results establish that the preimplantation mouse embryo is a target for
cannabinoid ligands. Consequently, many of the adverse effects of
cannabinoids observed during pregnancy could be mediated via these
cannabinoid receptors. Although the physiological significance of the
cannabinoid ligandreceptor signaling in normal preimplantation embryo
development is not yet clear, the regulation of embryonic cAMP and/or
Ca2+ levels via this signaling pathway may be important for
normal embryonic development and/or implantation.
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