title: Spatiotemporal expression of endogenous opioid processing enzymes in mouse uterus at peri-implantation.
abstract: Successful implantation requires intimate interactions between a competent blastocyst and a receptive uterus. We recently demonstrated that the aberrant activation of opioid signaling by exogenous ligands adversely affects preimplantation embryonic development and subsequent implantation in mice. However, the underlying machinery governing the dynamic homeostasis of the endogenous opioid system in the uterus during early pregnancy remains elusive. We now show that all three major endogenous opioid precursors are spatiotemporally expressed in the uterus during early pregnancy. Moreover, we observe the well-coordinated expression of the synthetic enzyme prohormone convertases 1/3 (PC1/3) at lower levels and of its inhibitor proprotein convertase subtilisin/kexin type 1 inhibitor (Pcsk1n) and the degrading enzyme membrane metallo-endopeptidase (MME) at higher levels in the receptive uterus. Both estrogen and progestin tend to reduce the uterine levels of opioid ligand precursors in the ovariectomized mouse model. This tight regulation of the endogenous opioid system by PC1/3, Pcsk1n and MME has been further confirmed in physiologically related pseudopregnancy and delayed implantation mouse models. The coordinated regulation of opioid precursor biosynthesis and metabolism helps to create appropriate opioid signaling ensuring uterine receptivity for implantation. Thus, endogenous uterine opioid levels are primarily determined by the coordinated expressions of PC1/3, Pcsk1n and MME under the influence of ovarian progestin and estrogen. Our findings raise an additional cautionary note regarding the effects of opioid abuse on early pregnancy events.
authors: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China.|University of Chinese Academy of Sciences, Beijing, 100039, People's Republic of China.
authors: Weiwei
authors: W
authors: Wu
authors: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China.
authors: Shuangbo
authors: S
authors: Kong
authors: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China.
authors: Bingyan
authors: B
authors: Wang
authors: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China. chenyongjie83@163.com.
authors: Yongjie
authors: Y
authors: Chen
authors: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China. hbwang@ioz.ac.cn.
authors: Haibin
authors: H
authors: Wang
mesh_terms: D000701:Analgesics, Opioid / Q000378:metabolism*; D000818:Animals; D010064:Embryo Implantation / Q000187:drug effects / Q000235:genetics; D004798:Enzymes / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D011247:Pregnancy; D011372:Progestins / Q000494:pharmacology; D045664:Proprotein Convertase 1 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D014599:Uterus / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000701:Analgesics, Opioid; D004798:Enzymes; D004967:Estrogens; D011372:Progestins; D012333:RNA, Messenger; D045664:Proprotein Convertase 1; D008666:Metalloendopeptidases
keywords: Mouse; Opioid; Peri-implantation; Synthetic and degrading enzymes; Uterus