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Aberrant cannabinoid signaling impairs oviductal transport of embryos

A Corrigendum to this article was published on 01 December 2004


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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Figure 1: Impaired oviductal embryo transport causes pregnancy loss in Cnr1−/− mice.
Figure 2: Analysis of Mbldc1, Cnr1 and Cnr2 mRNAs in the oviduct.
Figure 3: Aberrant cannabinoid signaling causes impaired oviductal embryo transport in wild-type mice.
Figure 4: Lack of CB1 increases oviductal nor-adrenaline release.
Figure 5: Normal embryo development and transport in Cnr1−/− mice are restored by prostaglandins and β-AR signaling, respectively.


  1. 1

    Hall, W. & Solowij, N. Adverse effects of cannabis. Lancet 352, 1611–6 (1998).

    CAS  Article  Google Scholar 

  2. 2

    Feng, T. Substance abuse in pregnancy. Curr. Opin. Obstet. Gynecol. 5, 16–23 (1993).

    CAS  Article  Google Scholar 

  3. 3

    Fergusson, D.M., Horwood, L.J. & Northstone, K. Maternal use of cannabis and pregnancy outcome. BJOG 109, 21–27 (2002).

    Article  Google Scholar 

  4. 4

    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).

    CAS  Article  Google Scholar 

  5. 5

    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).

    CAS  Article  Google Scholar 

  6. 6

    Munro, S., Thomas, K.L. & Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61–65 (1993).

    CAS  Article  Google Scholar 

  7. 7

    Devane, W.A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992).

    CAS  Article  Google Scholar 

  8. 8

    Sugiura, T. et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. 215, 89–97 (1995).

    CAS  Article  Google Scholar 

  9. 9

    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).

    CAS  Article  Google Scholar 

  10. 10

    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).

    CAS  Article  Google Scholar 

  11. 11

    Maccarrone, M. & Finazzi-Agro, A. Endocannabinoids and their actions. Vitam. Horm. 65, 225–255 (2002).

    CAS  Article  Google Scholar 

  12. 12

    Piomelli, D. The molecular logic of endocannabinoid signalling. Nat. Rev. Neurosci. 4, 873–884 (2003).

    CAS  Article  Google Scholar 

  13. 13

    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).

    CAS  Article  Google Scholar 

  14. 14

    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).

    CAS  Article  Google Scholar 

  15. 15

    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).

    CAS  Article  Google Scholar 

  16. 16

    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).

    CAS  Article  Google Scholar 

  17. 17

    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).

    CAS  Article  Google Scholar 

  18. 18

    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).

    CAS  Article  Google Scholar 

  19. 19

    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).

    Article  Google Scholar 

  20. 20

    Dennedy, M.C. et al. Cannabinoids and the human uterus during pregnancy. Am. J. Obstet. Gynecol. 190, 2–9 (2004).

    CAS  Article  Google Scholar 

  21. 21

    Maccarrone, M. et al. Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage. Lancet 355, 1326–1329 (2000).

    CAS  Article  Google Scholar 

  22. 22

    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).

    CAS  Article  Google Scholar 

  23. 23

    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).

    CAS  Article  Google Scholar 

  24. 24

    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).

    CAS  PubMed  Google Scholar 

  25. 25

    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).

    CAS  Article  Google Scholar 

  26. 26

    Schuel, H. et al. N-Acylethanolamines in human reproductive fluids. Chem. Phys. Lipids 121, 211–27 (2002).

    CAS  Article  Google Scholar 

  27. 27

    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).

    CAS  Article  Google Scholar 

  28. 28

    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).

    CAS  Article  Google Scholar 

  29. 29

    Godecke, A. et al. Coronary hemodynamics in endothelial NO synthase knockout mice. Circ. Res. 82, 186–194 (1998).

    CAS  Article  Google Scholar 

  30. 30

    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).

    CAS  Article  Google Scholar 

  31. 31

    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).

    CAS  Article  Google Scholar 

  32. 32

    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).

    CAS  Article  Google Scholar 

  33. 33

    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).

    CAS  Article  Google Scholar 

  34. 34

    Tolszczuk, M. & Pelletier, G. Autoradiographic localization of beta-adrenergic receptors in rat oviduct. Mol. Cell. Endocrinol. 60, 95–99 (1988).

    CAS  Article  Google Scholar 

  35. 35

    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).

    CAS  Article  Google Scholar 

  36. 36

    Arbab, F. et al. Prostacyclin is an autocrine regulator in the contraction of oviductal smooth muscle. Hum. Reprod. 17, 3053–3059 (2002).

    CAS  Article  Google Scholar 

  37. 37

    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).

    CAS  Article  Google Scholar 

  38. 38

    Centers for Disease Control and Prevention. Ectopic pregnancy-United States, 1990-1992. MMWR Morb. Mortal. Wkly. Rep. 44, 46–48. (1995).

  39. 39

    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).

    CAS  Article  Google Scholar 

  40. 40

    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).

    CAS  Article  Google Scholar 

  41. 41

    Saraiya, M. et al. Cigarette smoking as a risk factor for ectopic pregnancy. Am. J. Obstet. Gynecol. 178, 493–498 (1998).

    CAS  Article  Google Scholar 

  42. 42

    Yoshinaga, K., Rice, C., Krenn, J. & Pilot, R.L. Effects of nicotine on early pregnancy in the rat. Biol. Reprod. 20, 294–303 (1979).

    CAS  Article  Google Scholar 

  43. 43

    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).

    CAS  Article  Google Scholar 

  44. 44

    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).

    CAS  Article  Google Scholar 

  45. 45

    Song, H. et al. Cytosolic phospholipase A2alpha is crucial for 'on-time' embryo implantation that directs subsequent development. Development 129, 2879–2889 (2002).

    CAS  PubMed  Google Scholar 

  46. 46

    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).

    CAS  Article  Google Scholar 

  47. 47

    Comings, D.E. et al. Cannabinoid receptor gene (CNR1): association with i.v. drug use. Mol Psychiatry 2, 161–168 (1997).

    CAS  Article  Google Scholar 

  48. 48

    Ledent, C. et al. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283, 401–404 (1999).

    CAS  Article  Google Scholar 

  49. 49

    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).

    CAS  Article  Google Scholar 

  50. 50

    Kingsley, P.J. & Marnett, L.J. Analysis of endocannabinoids by Ag+ coordination tandem mass spectrometry. Anal. Biochem. 314, 8–15 (2003).

    CAS  Article  Google Scholar 

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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.

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Correspondence to Sudhansu K Dey.

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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)

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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).

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