Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hall, W. & Solowij, N. Adverse effects of cannabis. Lancet 352, 1611–6 (1998).
Feng, T. Substance abuse in pregnancy. Curr. Opin. Obstet. Gynecol. 5, 16–23 (1993).
Fergusson, D.M., Horwood, L.J. & Northstone, K. Maternal use of cannabis and pregnancy outcome. BJOG 109, 21–27 (2002).
Fried, P.A., Watkinson, B. & Gray, R. Differential effects on cognitive functioning in 13- to 16-year-olds prenatally exposed to cigarettes and marihuana. Neurotoxicol. Teratol. 25, 427–436 (2003).
Matsuda, L.A., Lolait, S.J., Brownstein, M.J., Young, A.C. & Bonner, T.I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561–564 (1990).
Munro, S., Thomas, K.L. & Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61–65 (1993).
Devane, W.A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992).
Sugiura, T. et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. 215, 89–97 (1995).
Sugiura, T. et al. Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor. Structure-activity relationship of 2-arachidonoylglycerol, ether-linked analogues, and related compounds. J. Biol. Chem. 274, 2794–2801 (1999).
Mechoulam, R. et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50, 83–90 (1995).
Maccarrone, M. & Finazzi-Agro, A. Endocannabinoids and their actions. Vitam. Horm. 65, 225–255 (2002).
Piomelli, D. The molecular logic of endocannabinoid signalling. Nat. Rev. Neurosci. 4, 873–884 (2003).
De Petrocellis, L., Cascio, M.G. & Di Marzo, V. The endocannabinoid system: a general view and latest additions. Br. J. Pharmacol. 141, 765–774 (2004).
Paria, B.C., Das, S.K. & Dey, S.K. The preimplantation mouse embryo is a target for cannabinoid ligand-receptor signaling. Proc. Natl. Acad. Sci. USA 92, 9460–9464 (1995).
Das, S.K., Paria, B.C., Chakraborty, I. & Dey, S.K. Cannabinoid ligand-receptor signaling in the mouse uterus. Proc. Natl. Acad. Sci. USA 92, 4332–4336 (1995).
Schmid, P.C., Paria, B.C., Krebsbach, R.J., Schmid, H.H. & Dey, S.K. Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation. Proc. Natl. Acad. Sci. USA 94, 4188–4192 (1997).
Wang, H. et al. Differential G protein-coupled cannabinoid receptor signaling by anandamide directs blastocyst activation for implantation. Proc. Natl. Acad. Sci. USA 100, 14914–14919 (2003).
Schuel, H., Goldstein, E., Mechoulam, R., Zimmerman, A.M. & Zimmerman, S. Anandamide (arachidonylethanolamide), a brain cannabinoid receptor agonist, reduces sperm fertilizing capacity in sea urchins by inhibiting the acrosome reaction. Proc. Natl. Acad. Sci. USA 91, 7678–7682 (1994).
Bisogno, T. et al. Occurrence and metabolism of anandamide and related acyl-ethanolamides in ovaries of the sea urchin Paracentrotus lividus. Biochim. Biophys. Acta 1345, 338–348 (1997).
Dennedy, M.C. et al. Cannabinoids and the human uterus during pregnancy. Am. J. Obstet. Gynecol. 190, 2–9 (2004).
Maccarrone, M. et al. Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage. Lancet 355, 1326–1329 (2000).
Compton, W.M., Grant, B.F., Colliver, J.D., Glantz, M.D. & Stinson, F.S. Prevalence of marijuana use disorders in the United States: 1991–1992 and 2001–2002. JAMA 291, 2114–2121 (2004).
Zimmer, A., Zimmer, A.M., Hohmann, A.G., Herkenham, M. & Bonner, T.I. Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl. Acad. Sci. USA 96, 5780–5785 (1999).
Das, S.K. et al. Heparin-binding EGF-like growth factor gene is induced in the mouse uterus temporally by the blastocyst solely at the site of its apposition: a possible ligand for interaction with blastocyst EGF-receptor in implantation. Development 120, 1071–1083 (1994).
Okamoto, Y., Morishita, J., Tsuboi, K., Tonai, T. & Ueda, N. Molecular characterization of a phospholipase D generating anandamide and its congeners. J. Biol. Chem. 279, 5298–5305 (2004).
Schuel, H. et al. N-Acylethanolamines in human reproductive fluids. Chem. Phys. Lipids 121, 211–27 (2002).
Racz, I. et al. A critical role for the cannabinoid CB1 receptors in alcohol dependence and stress-stimulated ethanol drinking. J. Neurosci. 23, 2453–2458 (2003).
Sage, J., Miller, A.L., Perez-Mancera, P.A., Wysocki, J.M. & Jacks, T. Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 424, 223–228 (2003).
Godecke, A. et al. Coronary hemodynamics in endothelial NO synthase knockout mice. Circ. Res. 82, 186–194 (1998).
Halbert, S.A., Tam, P.Y. & Blandau, R.J. Egg transport in the rabbit oviduct: the roles of cilia and muscle. Science 191, 1052–1053 (1976).
Heilman, R.D., Reo, R.R. & Hahn, D.W. Changes in the sensitivity of adrenergic receptors in the oviduct during early gestation in the rabbit. Fertil. Steril. 27, 426–430 (1976).
Howe, G.R. & Black, D.L. Autonomic nervous system and oviduct function in the rabbit. I. Hormones and contraction. J. Reprod. Fertil. 33, 425–430 (1973).
Kennedy, D.R. & Marshall, J.M. Effect of adrenergic nerve stimulation on the rabbit oviduct: correlation with norepinephrine content and turnover rate. Biol. Reprod. 16, 200–211 (1977).
Tolszczuk, M. & Pelletier, G. Autoradiographic localization of beta-adrenergic receptors in rat oviduct. Mol. Cell. Endocrinol. 60, 95–99 (1988).
Roblero, L.S. & Garavagno, A.C. Effect of oestradiol-17 beta and progesterone on oviductal transport and early development of mouse embryos. J. Reprod. Fertil. 57, 91–95 (1979).
Arbab, F. et al. Prostacyclin is an autocrine regulator in the contraction of oviductal smooth muscle. Hum. Reprod. 17, 3053–3059 (2002).
Huang, J.C. et al. Human fallopian tubes express prostacyclin (PGI) synthase and cyclooxygenases and synthesize abundant PGI. J. Clin. Endocrinol. Metab. 87, 4361–4368 (2002).
Centers for Disease Control and Prevention. Ectopic pregnancy-United States, 1990-1992. MMWR Morb. Mortal. Wkly. Rep. 44, 46–48. (1995).
Schlicker, E., Redmer, A., Werner, A. & Kathmann, M. Lack of CB1 receptors increases noradrenaline release in vas deferens without affecting atrial noradrenaline release or cortical acetylcholine release. Br. J. Pharmacol. 140, 323–328 (2003).
Deutsch, D.G. et al. Production and physiological actions of anandamide in the vasculature of the rat kidney. J. Clin. Invest. 100, 1538–1546 (1997).
Saraiya, M. et al. Cigarette smoking as a risk factor for ectopic pregnancy. Am. J. Obstet. Gynecol. 178, 493–498 (1998).
Yoshinaga, K., Rice, C., Krenn, J. & Pilot, R.L. Effects of nicotine on early pregnancy in the rat. Biol. Reprod. 20, 294–303 (1979).
Gonzalez, S. et al. Changes in endocannabinoid contents in the brain of rats chronically exposed to nicotine, ethanol or cocaine. Brain Res. 954, 73–81 (2002).
Wilcox, A.J., Baird, D.D. & Weinberg, C.R. Time of implantation of the conceptus and loss of pregnancy. N. Engl. J. Med. 340, 1796–1799 (1999).
Song, H. et al. Cytosolic phospholipase A2alpha is crucial for 'on-time' embryo implantation that directs subsequent development. Development 129, 2879–2889 (2002).
Gadzicki, D., Muller-Vahl, K. & Stuhrmann, M. A frequent polymorphism in the coding exon of the human cannabinoid receptor (CNR1) gene. Mol. Cell Probes 13, 321–323 (1999).
Comings, D.E. et al. Cannabinoid receptor gene (CNR1): association with i.v. drug use. Mol Psychiatry 2, 161–168 (1997).
Ledent, C. et al. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283, 401–404 (1999).
Jarai, Z. et al. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc. Natl. Acad. Sci. USA 96, 14136–14141 (1999).
Kingsley, P.J. & Marnett, L.J. Analysis of endocannabinoids by Ag+ coordination tandem mass spectrometry. Anal. Biochem. 314, 8–15 (2003).
Acknowledgements
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Fig. 1
CB1 deficiency causes pregnancy loss in mice (PDF 139 kb)
Supplementary Table 1
Treatment with phenylephrine alone or in combination with butoxamine in wild-type pregnant mice leads to oviductal retention of embryos (PDF 18 kb)
Supplementary Table 2
Supplementation with progesterone or estrogen fails to restore normal embryo transport in Cnr1−/− mice (PDF 18 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1104
This article is cited by
-
CFP1 governs uterine epigenetic landscapes to intervene in progesterone responses for uterine physiology and suppression of endometriosis
Nature Communications (2023)
-
Control of oviductal fluid flow by the G-protein coupled receptor Adgrd1 is essential for murine embryo transit
Nature Communications (2021)
-
Adrenomedullin insufficiency alters macrophage activities in fallopian tube: a pathophysiologic explanation of tubal ectopic pregnancy
Mucosal Immunology (2020)
-
Delta-9 THC can be detected and quantified in the semen of men who are chronic users of inhaled cannabis
Journal of Assisted Reproduction and Genetics (2020)
-
Prenatal cannabinoid exposure alters the ovarian reserve in adult offspring of rats
Archives of Toxicology (2020)