Preimplantation Mouse Embryo Is a Target for Opioid Ligand-Receptor Signaling1

Abstract

Synchronization of preimplantation embryo development to blastocysts is one of the prerequisites for normal embryo implantation. While previous studies have ascribed an adverse effect to aberrant opioid signaling on embryo and fetal development, it has remained unclear whether the opioid system is operative in early pregnancy events. In the present study, employing multiple pharmacological and genetic approaches, we demonstrated that preimplantation embryos spanning the zygote to blastocyst express the opioid receptor subtypes and the oviduct expresses endogenous opioid precursors dynamically, which suggest that opioid signaling is functionally operative during preimplantation embryo development. Subsequent analysis further revealed that an aberrantly activated opioid signaling by morphine can remarkably derail normal preimplantation embryo development via inhibiting intracellular calcium mobilization, while a cotreatment of naloxone with morphine can remarkably reverse the adverse effects of morphine on preimplantation embryo development. Besides shedding light on the pathophysiological significance of the opioid system during early embryo development in mice, our findings have potential clinical relevance because an abused use of illicit opiate drugs is frequently associated with retarded fetal development and pregnancy failure in women.

Spatiotemporal expression of endogenous opioid processing enzymes in mouse uterus at peri-implantation

“…This coordination between endogenous opioid precursor synthesis by PC1/3 and degradation via MME plus the extra Bguidance^from Pcsk1n might help to create and maintain a low level of active opioid peptides that might be beneficial for uterine transformation prior to implantation. Indeed, our previous study demonstrated a similar phenomenon of a tightly regulated endogenous opioid system and the endocannabinoid system by the biosynthetic and metabolic pathway in the oviduct during preimplantation embryonic development (Chen et al 2014;). This notion is further confirmed by our observations obtained in pseudopregnant day 4 receptive versus day 6 refractory uteri and in the physiologically relevant delayed implantation mouse model.…”

“…Our previous study revealed that opioid receptor subtypes are dynamically expressed in preimplantation embryos (Chen et al 2014). With respect to the pathophysiological significance of opioid signaling in Pcsk1n (f, f') in ovariectomized mouse uteri treated with oil (Oil), estradiol-17β (E2), or progesterone (P4).…”

“…The endogenous cannabinoid ligand anandamide produced by the uterus and the cannabinoid receptor CB1 expressed in the blastocyst are coordinately downregulated upon the uterus entering the receptive phase and the blastocyst achieving implantation competency. In this respect, our recent work established that the preimplantation embryo is a potential target of endogenous opioid signaling, since the oviduct can produce opioid precursors, whereas early embryos express opioid receptors (Chen et al 2014). Moreover, we most recently demonstrated that an excessive activation of opioid signaling by exogenous ligand morphine disrupts normal uterine receptivity, resulting in implantation failure (Tang et al 2015).…”

“…Moreover, the endogenous levels of active opioid peptides also largely depend on the expression and activity of an opioid-degrading enzyme, namely membrane metallo-endopeptidase (MME, also known as NEP; Benjannet et al 1991;Peinado et al 2003;Zhou and Lindberg 1993). Since aberrantly enhanced opioid signaling by morphine adversely affects peri-implantation events (Chen et al 2014;Tang et al 2015), the synthetic enzyme PC and its inhibitor Pcsk1n together with the degrading enzyme MME might coordinately regulate endogenous opioid levels during early pregnancy. Therefore, an exploration of the cellular and stagedependent expression profiles of the opioid processing enzymes, PCs, Pcsk1n and MME in the peri-implantation uterus would be meaningful.…”

Systemic Morphine Treatment Derails Normal Uterine Receptivity, Leading to Embryo Implantation Failure in Mice1

“…Moreover, illicit use of opioids during pregnancy is often associated with adverse pregnancy outcomes, such as poor fetal growth, preterm delivery, and fetal death [11][12][13][14][15][16][17]. In this respect, our recent study revealed while the opioid signaling is functionally operative during preimplantation embryo development, an aberrantly activated opioid signaling by morphine can remarkably impair the normal preimplantation embryo development via inhibiting intracellular calcium mobilization [18]. However, it remained largely unexplored regarding the pathophysiological significance of opioid system on uterine functions at periimplantation.…”