The preimplantation mouse embryo is a target for cannabinoid ligand-receptor signaling.

Paria, Bibhash C.; Das, Sanjoy K.; Dey, Sudhansu K.

doi:10.1073/pnas.92.21.9460

Cited by 178 publications

(166 citation statements)

References 31 publications

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“…Higher uterine levels during the nonreceptive phase on day 5 of pseudopregnancy suggest that embryotoxic effects of the uterine environment during this time (15) could be due to increased anandamide levels. This suggestion is consistent with our observation that anandamide inhibits development of two-cell embryos to blastocysts in vitro (12,13) and zonahatching of blastocysts developed from eight-cell embryos in vitro ( Table 2), and that these detrimental effects of anandamide are reversed by SR141716A. Furthermore, infusion of a synthetic cannabinoid ligand CP 55,940 via miniosmotic pumps during the preimplantation period prevented implanPhysiology: Schmid et al…”

Section: Resultssupporting

confidence: 80%

“…Also, activation of CB1-R by cannabinoid ligands including anandamide interferes with preimplantation embryo development, and this effect is completely reversed by a specific CB1-R antagonist (13). These results and anandamide synthetic capacity of the periimplantation mouse uterus (11,12,14) suggested that cannabinoid-ligand receptor signaling during implantation could be physiologically and pharmacologically important.…”

mentioning

confidence: 60%

“…We recently discovered that the CB1-R gene is expressed in the periimplantation mouse uterus and embryo, and the levels of CB1-R in the embryo, are much higher than those in the brain (11)(12)(13). Also, activation of CB1-R by cannabinoid ligands including anandamide interferes with preimplantation embryo development, and this effect is completely reversed by a specific CB1-R antagonist (13).…”

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confidence: 99%

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Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation

Schmid

Paria

Krebsbach

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

239

166

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Anandamide (N-arachidonoylethanolamine) is an endogenous ligand for both the brain-type (CB1-R) and spleen-type (CB2-R) cannabinoid receptors. This investigation demonstrates that the periimplantation mouse uterus contains the highest levels of anandamide (142-1345 pmol͞ mol lipid P; 1-7 g͞g wet weight) yet discovered in a mammalian tissue. The levels f luctuate with the state of pregnancy; down-regulation of anandamide levels is associated with uterine receptivity, while up-regulation is correlated with uterine refractoriness to embryo implantation. Anandamide levels are highest during the nonreceptive phase in the pseudopregnant uterus and in the interimplantation sites, and lowest at the site of embryo implantation. The lower levels of uterine anandamide at the implantation sites may be a mechanism by which implanting embryos protect themselves from the detrimental effects of this endogenous ligand. We also observed a reduced rate of zona-hatching of blastocysts in vitro in the presence of anandamide, and inhibition of implantation by systemic administration of a synthetic cannabinoid agonist CP 55,940. These adverse effects were reversed by SR141716A, a specific CB1-R antagonist. Taken together, the results suggest that an aberrant synthesis of anandamide and͞or expression of the cannabinoid receptors in the uterus͞embryo may account for early pregnancy failure or female infertility.

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Section: Resultssupporting

confidence: 80%

mentioning

confidence: 60%

mentioning

confidence: 99%

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Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation

Schmid

Paria

Krebsbach

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

239

166

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“…In contrast, CNR2 is expressed in embryos from 1-cell through the blastocyst stage, but in the latter stage, CNR2 expression is primarily restricted to the ICM. 31 In the oviduct and uterus, only CNR1, but not CNR2, is detected. 32,33 In addition to the presence of these two receptors, FAAH and NAPE-PLD are also present in the preimplantation embryos from the 2-cell stage to the blastocyst stage.…”

Section: Endocannabinoid Signaling In the Mousementioning

confidence: 99%

“…The development of 2-cell embryos to blastocysts was shown to be arrested at high levels of AEA, 2-AG, Δ 9 -THC, or a synthetic cannabinoid agonist WIN55212-2. 31,34 Moreover, blastocysts treated with high levels of AEA had a reduced number of TE cells, and blastocyst zona-hatching became sluggish. 35,36 The adverse effects of high level cannabinoid/endocannabinoid signaling was attenuated by SR141716A and AM251 (CNR1 selective antagonists), but not by SR144528 (a CNR2 specific antagonist).…”

Section: Endocannabinoid Signaling In the Mousementioning

confidence: 99%

Endocannabinoid Signaling in Female Reproduction

Sun

Dey

2012

ACS Chem. Neurosci.

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Marijuana is a preparation of the flower, as well as the leaves and seeds, of the plant Cannabis sativa. Marijuana has been used for medicinal and recreational purposes for thousands of years due to its psychoactive effects including euphoria, sedation, and analgesia. Although it has been suspected for decades that marijuana has adverse effects on female fertility, the underlying molecular mechanism was not clear. The discovery of cannabinoid receptors and endocannabinoids has advanced studies if cannabinoid signaling. Since then, numerous studies have been published on cannabinoid signaling in female reproductive events, including preimplantation embryo development, oviductal embryo transport, embryo implantation, placentation, and parturition. This review focuses on various aspects of endocannabinoid signaling in female fertility.

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Analysis of cannabinoid receptor binding and mRNA expression and endogenous cannabinoid contents in the developing rat brain during late gestation and early postnatal period

Berrendero

Sepe

Ramos

et al. 1999

Synapse

266

124

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Cannabinoid CB(1) receptors emerge early in the rat brain during prenatal development, supporting their potential participation in events related to neural development. In the present investigation, we completed earlier studies, analyzing CB(1) receptor binding and mRNA expression by using autoradiography and in situ hybridization, respectively, in the brain of rat fetuses at gestational day (GD) 21 and of newborns at postnatal days (PND) 1 and 5, in comparison with the adult brain. These analyses were paralleled by quantitation of levels of anandamide and its precursor, N-arachidonoyl-phosphatidylethanolamine (NAPE), and of 2-arachidonoyl-glycerol (2-AG), carried out by using gas chromatography / mass spectrometry of the tri-methyl-sylyl-ether derivatives. As expected, CB(1) receptor binding was detected at GD21 in a variety of brain structures. In most of them, such as the hippocampus, cerebral cortex, cerebellum, basal ganglia, and limbic nuclei, there were no marked differences in the density of CB(1) receptors in animals at GD21 as compared to early newborns (PND1 and 5), although it markedly increased in these regions in adulthood. However, with the exception of the cerebellum and, in part, the caudate-putamen, the pattern observed for binding in these regions was clearly different from that observed for mRNA expression of the CB(1) receptor, which currently exhibited the highest levels at PND1 and the lowest in the adult brain. This was also seen in the basolateral amygdaloid nucleus, ventromedial hypothalamic nucleus, medial habenula, and other structures. In the caudate-putamen and, particularly, in the cerebellum, mRNA expression was higher in the adult brain as compared with other ages. As previously reported, specific binding for CB(1) receptors was also detected at GD21 in white matter areas, such as the corpus callosum, anterior commissure, fornix, fimbria, stria medullaris, stria terminalis, and fasciculus retroflexum. With the exception of the anterior commissure and the fimbria, specific binding progressively decreased at PND1 and PND5 until disappearing in the adult brain. In the fimbria, the highest values of binding were seen at PND1, but binding also completely disappeared in the adult brain, whereas in the anterior commissure, specific binding at PND1 and PND5 was lesser than that observed at GD21 and, particularly, in adulthood. CB(1) receptor mRNA expression was not detected in these white matter areas, thus dismissing the possible presence of these receptors in glial cells rather than in neuronal axons. However, mRNA expression was detected in the brainstem, an area also rich in white matter, and it mostly correlated with receptor binding, exhibiting a progressive decrease from GD21 up to adulthood. CB(1) receptor mRNA expression was also detected at GD21 in atypical areas where binding was not detected. These areas are proliferative regions, such as the subventricular zones of the neocortex, striatum, and nucleus accumbens. This atypical location only persisted at PND1 and PND5 in the st...

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The preimplantation mouse embryo is a target for cannabinoid ligand-receptor signaling.

Cited by 178 publications

References 31 publications

Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation

Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation

Endocannabinoid Signaling in Female Reproduction

Analysis of cannabinoid receptor binding and mRNA expression and endogenous cannabinoid contents in the developing rat brain during late gestation and early postnatal period

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