CONICET | Buscador de Institutos y Recursos Humanos

Anandamide (AEA), an endocannabinoid, and nitric oxide (NO) are important mediators of implantation. AEA exerts part of its effects binding to cannabinoid receptors type 1 (CB1) and type 2 (CB2). We observed that nitric oxide synthase (NOS) activity in the rat uterus remained high on days 4 and 5 of pregnancy and at implantation sites on day 6, when compared to day 6 inter-implantation sites. Both dormant and active blastocysts seemed to increase NOS activity. As AEA level presents an inverted pattern compared to NOS, we studied if AEA modulated NOS activity during peri-implantation. First, we investigated AEA effect in pseudopregnant rats (psp), a model in which embryos are absent, to discard blastocysts as a possible source of AEA and as a modulator of NOS activity. AEA inhibited NOS activity only on day 5 of psp through CB2 receptors. Methanandamide (a non-hydrolysable AEA synthetic analogue) and URB-597 (an enhancer of AEA level) also inhibited NOS activity via CB2 receptors. However during normal gestation, incubation of day 6 implantation sites with URB-597 decreased NOS activity through CB1 receptors, while incubation of day 6 inter-implantation sites with a CB2 antagonist augmented NOS activity. These results suggest that AEA modulated NOS activity through CB1 or CB2 receptors depending on the presence of the blastocyst. Low AEA levels close to and at implantation sites could increase uterine NOS activity and thus NO production, fundamental for implantation, via CB1. Maternal ovarian hormones and blastocysts seemed to contribute to this modulation.