CHANGES IN ANANDAMIDE LEVELS IN MOUSE UTERUS ARE ASSOCIATED WITH UTERINE RECEPTIVITY FOR EMBRYO IMPLANTATION

Anandamide (N-arachidonoylethanolamine) is an endogenous ligand for bo th the brain-type (CB1-R) and spleen-type (CB2-R) cannabinoid receptor s. This investigation demonstrates that the periimplantation mouse ute rus contains the highest levels of anandamide (142-1345 pmol/mu mol li pid P; 1-7 mu g/g wet weight) yet discovered in a mammalian tissue. Th e levels fluctuate with the state of pregnancy; down-regulation of ana ndamide levels is associated with uterine receptivity, while up-regula tion is correlated with uterine refractoriness to embryo implantation. Anandamide levels are highest during the nonreceptive phase in the ps eudopregnant uterus and in the interimplantation sites, and lowest at the site of embryo implantation. The lower levels of uterine anandamid e at the implantation sites may be a mechanism by which implanting emb ryos protect themselves from the detrimental effects of this endogenou s ligand. We also observed a reduced rate of zona-hatching of blastocy sts in vitro in the presence of anandamide, and inhibition of implanta tion by systemic administration of a synthetic cannabinoid agonist CP 55,940. These adverse effects were reversed by SR141716A, a specific C B1-R antagonist. Taken together, the results suggest that an aberrant synthesis of anandamide and/or expression of the cannabinoid receptors in the uterus/embryo may account for early pregnancy failure or femal e infertility.