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

Abstract

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.

A Critical Interaction between Dopamine D2 Receptors and Endocannabinoids Mediates the Effects of Cocaine on Striatal GABAergic Transmission

“…It should be noted that the levels of AEA found here are comparable to those found in the striatum of healthy and parkinsonian rats (Gubellini et al, 2002), but higher than those found by others in rat brain (Yang et al, 1999). However, our values are in the same range as the endogenous levels of AEA in rat substantia nigra and globus pallidus (Di Marzo et al, 2000), in mouse cortex and hippocampus (Maccarrone et al, 2001), and in mouse uterus (Schmid et al, 1997). In addition, we have recently measured by our GC-MS procedure the levels of AEA in human T lymphocytes treated or not with progesterone, and found differences superimposable to those found in the same samples in Dr Kunos' laboratory at NIAAA-NIH by liquid chromatography-mass spectrometry (reported in Maccarrone et al, 2003b).…”

Endocannabinoid Signaling in Female Reproduction

“…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). These results were further confirmed by the observation that a CNR2 agonist, AM663, failed to affect embryo development.…”

“…High levels of AEA or other synthetic cannabinoids inhibited blastocyst zona-hatching, while low levels of AEA accelerated trophoblast differentiation and outgrowth in culture. 31,34,36 To minimize exposure to endocannabinoid signaling, the expression of CNR1 is downregulated in the blastocyst approaching implantation. For example, WT blastocysts collected from the uterus on the morning of day 4 of pregnancy had higher levels of AEA binding compared with blastocysts recovered in the evening of day 4 prior to the attachment reaction, suggesting that regulated signaling by AEA is beneficial for the implantation competency of blastocysts.…”

THC: moderation during implantation

“…Before it becomes receptive, the uterus contains exceedingly high levels of anandamide-higher, in fact, than anywhere else in the body 7 . As the tissue progresses into receptivity, anandamide concentrations drop, suggesting that a lower cannabinoid tone creates a friendlier environment for implantation.…”

“…In a series of landmark studies, Dey and colleagues have established that cannabinoid receptors and their endogenous activator, anandamide 6 , are integral components of this network 5,7,8 .…”