Ectopic pregnancy is a major reproductive health issue. Although other underlying causes remain largely unknown, one cause of ectopic pregnancy is embryo retention in the fallopian tube. Here we show that genetic or pharmacologic silencing of cannabinoid receptor CB1 causes retention of a large number of embryos in the mouse oviduct, eventually leading to pregnancy failure. This is reversed by isoproterenol, a β-adrenergic receptor agonist. Impaired oviductal embryo transport is also observed in wild-type mice treated with methanandamide. Collectively, the results suggest that aberrant cannabinoid signaling impedes coordinated oviductal smooth muscle contraction and relaxation crucial to normal oviductal embryo transport. Colocalization of CB1 and β2-adrenergic receptors in the oviduct muscularis implies that a basal endocannabinoid tone in collaboration with adrenergic receptors coordinates oviductal motility for normal journey of embryos into the uterus. Besides uncovering a new regulatory mechanism, this study could be clinically relevant to ectopic pregnancy.
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We thank T. Bonner and A. Zimmer for providing us initially with the Cnr mutant mice for establishing colonies in our animal facilities. This work was supported in part by the National Institutes of Health (NIH) Grants (DA06668, HD12304, HD37830 & CA77839) and National Foundation for Cancer Research. S.K. Dey is recipient of Method to Extend Research in Time (MERIT) Awards from the National Institute on Drug Abuse (NIDA) and the National Institute of Child Health and Human Development (NICHD). H. Wang is a Lalor Foundation Fellow.
The authors declare no competing financial interests.
CB1 deficiency causes pregnancy loss in mice (PDF 139 kb)
Treatment with phenylephrine alone or in combination with butoxamine in wild-type pregnant mice leads to oviductal retention of embryos (PDF 18 kb)
Supplementation with progesterone or estrogen fails to restore normal embryo transport in Cnr1−/− mice (PDF 18 kb)
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Wang, H., Guo, Y., Wang, D. et al. Aberrant cannabinoid signaling impairs oviductal transport of embryos. Nat Med 10, 1074–1080 (2004). https://doi.org/10.1038/nm1104
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