Originally published In Press as doi:10.1074/jbc.M100679200 on March 8, 2001 free PDF
J. Biol. Chem., Vol. 276, Issue 23, 20523-20528, June 8, 2001
Dysregulated Cannabinoid Signaling Disrupts Uterine Receptivity for Embryo Implantation*
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From the Department of Pediatrics and the § Department of Molecular and Integrative Physiology, Ralph L. Smith Research Center, University of Kansas Medical Center, Kansas City, Kansas 66160-7338, the ¶ Hormel Institute, University of Minnesota, Austin, Minnesota 55912, the Laboratory of Genetics, National Institute of Mental Health, Bethesda, Maryland 20892, and the** Laboratory of Molecular Neurobiology, Clinic of Psychiatry, University of Bonn, 53105 Bonn, Germany
The mechanisms by which synchronized embryonic development to the blastocyst stage, preparation of the uterus for the receptive state, and reciprocal embryo-uterine interactions for implantation are coordinated are still unclear. We show in this study that preimplantation embryo development became asynchronous in mice that are deficient in brain-type (CB1) and/or spleen-type (CB2) cannabinoid receptor genes. Furthermore, whereas the levels of uterine anandamide (endocannabinoid) and blastocyst CB1 are coordinately down-regulated with the onset of uterine receptivity and blastocyst activation prior to implantation, these levels remained high in the nonreceptive uterus and in dormant blastocysts during delayed implantation and in pregnant, leukemia inhibitory factor (LIF)-deficient mice with implantation failure. These results suggest that a tight regulation of endocannabinoid signaling is important for synchronizing embryo development with uterine receptivity for implantation. Indeed this is consistent with our finding that while an experimentally induced, sustained level of an exogenously administered, natural cannabinoid inhibited implantation in wild-type mice, it failed to do so in CB1
//CB2/ double mutant mice. The present study is clinically important because of the widely debated medicinal use of cannabinoids and their reported adverse effects on pregnancy.
* This work was supported by National Institutes of Health Grants DA 06668, HD 12304, and HD 29968 (to S. K. D.), HD 37394 (to B. C. P.), and GM 45741 (to H. H. O. S.) and by the Hormel Foundation (to H. H. O. S.). Center grants in Reproductive Biology (HD 33994) and Mental Retardation (HD 02528) provided access to various core facilities.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
NICHD/National Institutes of Health Method to Extend Research in Time (MERIT) awardee.
§§ To whom correspondence should be addressed: Dept. of Molecular and Integrative Physiology, 3901 Rainbow Blvd., Kansas City, KS 66160-7338. Tel.: 913-588-6213; Fax: 913-588-5677; E-mail: sdey@kumc.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.