Tocolytic Effect of Δ9-Tetrahydrocannabinol in Mice Model of Lipopolysaccharide—Induced Preterm Delivery: Role of Nitric Oxide

Abstract

Introduction: In this study, we explained that exogenous cannabinoid, Δ⁹-tetrahydrocannabinol (THC), has a preventive effect in a murine model of lipopolysaccharide (LPS)-induced preterm delivery and the contribution of nitric oxide (NO) pathway as a mechanism involved in this process. Study Design: Preterm delivery was induced by double dose of 35 µg/kg LPS with 3-hour interval on gestational day (gd) 15. Δ⁹-tetrahydrocannabinol was administered with (a) double dose (0.02, 0.05, 0.1, 0.5, 1, and 5 mg/kg) 1 hour before each LPS injection, on gd 15 and (b) single administration (0.05, 0.1, and 0.5 mg/kg,) on gds 13 and 14, and the double administration, 1 hour before each LPS injection. To assess the involved mechanism, either AM281 (CB1 receptor antagonist, 2 mg/kg) and AM630 (CB2 receptor antagonist, 5 mg/kg) or N^ω-nitro-L-arginine methyl ester (L-NAME, 2 mg/kg) was administered 1 hour before each THC injection on gds 13, 14, and 15. The main outcome measurement was the incidence of preterm delivery after injection of last LPS dose. Any interaction in the incidence and time of preterm delivery was ruled out by administration of AM281, AM630, or L-NAME alone. Results: Chronic THC treatment (0.5 mg/kg) significantly decreased the incidence of LPS-induced premature labor and increased the delivery time. Both AM281 and L-NAME reversed THC-induced attenuation of preterm delivery rate and pregnancy duration. Unlike AM281, AM630 did not influence the rate of preterm delivery in THC-treated mice. Conclusion: Δ⁹-Tetrahydrocannabinol contributes to the regulation of gestational duration in LPS-induced preterm delivery probably by NO coupling through the CB1 receptor.

Keywords

Cannabinoid lipopolysaccharide preterm delivery nitric oxide mice.

Get full access to this article

View all access options for this article.

References

Dudley DJ , Chen C. , Branch DW , Hammond E. , Mitchell MD A murine model of preterm labor: inflammatory mediators regulate the production of prostaglandin E2 and interlukin-6 by murine decidua. Biol Reprod. 1993;48(1):33-39.

Loftin CD , Trivedi DB , Langenbach R. Cyclooxygenase-1-selective inhibition prolongs gestation in mice without adverse effects on the ductus arterious. J Clin Invest. 2002; 110(4):549-557.

Romero R. , Mazor M. Infection and preterm labor. Clin Obstet Gynecol. 1988;31(3):553-584.

Xu DX , Wang H. , Zhao L. , Ning H. , Chen YH , Zhang C. Effects of low dose lipopolysaccharide (LPS) pretreatment on LPS-induced intrauterine fetal death and preterm labor. Toxicology. 2007;234(3):167-175.

Katsuki Y. , Kaga N. , Kakinuma C. , Takagaki K. , Kajikawa S. , Shibutani Y. Ability of intrauterine bacterial lipopolysaccharide to cause in situ uterine contractions in pregnant rabbits. Acta Obstet Gynecol Scand . 1997;76(1):26-32.

Kaga N. , Katsuki Y. , Satoshi K. , Shibutani Y. Preventive effect of ritodrine hydrochloride and/or urinary trypsin inhibitor against lipopolysaccharide-induced preterm delivery in mice. Acta Obstet Gynecol Scand. 1997;76(9):811-816.

Gross G. , Imamura T. , Vogt SK , et al. Inhibition of cyclooxygenase-2 prevents inflammation-mediated preterm labor in the mouse. Am J Physiol Regul Integr Comp Physiol. 2000;278(6):1415-1423.

Paria BC , Dey SK Ligand receptor signaling with endocannabinoids in primplantation embryo development and implantation. Chem Phys Lipids. 2000;108(1-2):211-220.

Park B. , Gibbons HM , Mitchell MD , Glass M. Identification of the CB1 cannabinoid receptor and fatty acid amide hydrolase (FAAH) in the human placenta. Placenta. 2003 ;24(10):990-995.

10.

Das SK , Paria BC , Chakraborty I. , Dey SK Cannabinoid ligand-receptor signaling in the mouse uterus. Proc Natl Acad Sci U S A. 1995;92(10):4332-4336.

11.

Wang H. , Xie H. , Dey SK Loss of cannabinoid receptor CB1 induced preterm birth. Plos One. 2008;3(10):1-8.

12.

Schmid P. , Paria BC , Krebsbach RJ , Schmid HHO , Dey SK Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation. Proc Natl Acad Sci U S A. 1997;94(8):4188-4192.

13.

Wenger T. , Croix D. , Tramu G. , et al. Marijuana and reproduction. Effects on puberty and gestation in female rats. Experimental results. Ann Endocrinol. 1992;53(1):37-43.

14.

Moncada SR , Palmer MG , Higgs EA Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev. 1995;43(2):109-142.

15.

Buhimschi I. , Ali M. , Jain V. , Chwalisz K. , Garfield RE Differential regulation of nitric oxide in the rat uterus and cervix during pregnancy and labour. Hum Reprod. 1996;11(8):1755-1766.

16.

Yallampalli C. , Garfield RE , Byam-Smith M. Nitric oxide inhibits uterine contractility during pregnancy but not during delivery. Endocrinology. 1993;133(4):1899-1902.

17.

Tiboni GM , Glampietro F. Inhibition of nitric oxide synthesis causes preterm delivery in the mouse . Hum Reprod. 2000; 15(8):1838-1842.

18.

Romano MR , Lograno MD Cannabinoid agonists induce relaxation in the bovine ophthalmic artery: evidence for CB1 receptors, nitric oxide and potassium channels. Br J Pharmacol. 2006;147(8):917-925.

19.

Mukhopadhyay S. , Chapnick BM , Howlett AC Anandamide-induced vasorelaxation in rabbit aortic rings has two components: Gprotein dependent and independent. Am J Physiol Circ Physiol. 2002;282(6):H2048-H2054.

20.

Javadi-Paydar M. , Lesani A. , Vakilipour R. , et al. Evaluation of the tocolytic effect of morphine in a mouse model of lipopolysaccharide-induced preterm delivery: the role of nitric oxide. Eur J Obstet Gynecol Reprod Biol . 2009;147(2):166-172.

21.

Athanassakis I. , Aifantis I. , Randella A. , Giouremou K. , Vassiliadis S. Inhibition of nitric oxide production rescues LPS-induced fetal abortion in mice. Nitric Oxide. 1999;3(3):216-224.

22.

Dennedy MC , Friel AM , Houlihan DD , Broderick VM , Smith T. , Morrison JJ Cannabinoids and the human uterus during pregnancy. Am J Obstet Gynecol. 2004;190(1):2-9.

23.

Fride E. The endocannabinoid-CB1 receptor system in pre and postnatal life . Eur J Pharmacol. 2004;500(1-3):289-297.

24.

Nakano M. , Qura N. , Ochiai K. , Terajima Y. The contractility of uterine smooth muscle from pregnant rats infected intraperitoneally . Acta Obstet Gynaecol Jpn. 1994;46(Suppl):S406.

25.

Ross RG , Sathishkumar K. , Naik AK , et al. Mechanisms of lipopolysaccharide-induced changes in effects of contractile agonists on pregnant rat myometrium. Am J Obstet Gynecol. 2004;190(2):532-540.

26.

Wenger T. , Toth BE , Jauneda C. , et al. The effects of cannabinoids on the regulation of reproduction . Life Sci. 1999; 65(6-7):695-701.

27.

Wenger T. , Fragkakis G. , Giannikou K. , et al. Effects of anandamide on gestation in pregnant rats. Life Sci. 1997;60(26): 2361-2371.

28.

Mc Kay DG , Wong TC The effect of bacterial endotoxin on the placenta of the rat. Am J Pathol. 1963 ;42(3):357-377.

29.

Bradely SG , Munson AE , Dewey WL , Harris LS Enhanced susceptibility of mice to combination of Δ9-tetrahydrocannabinol and live or killed gram-negative bacteria. Infect Immun. 1977; 17(2):325-329.

30.

Cella M. , Leguizamon GF , Sordelli MS , et al. Dual effect of anandamide on rat placenta nitric oxide synthesis . Placenta. 2008;29(8):690-707.

31.

Thanda M. , Saheki S. , Kitagawa H. , Yano J. , Matsura S. Gestational changes in nitric oxide synthase activity in the rat placenta . J Obstet Gynecol Res. 1996;22(3): 267-273.

32.

Chwalisz K. , Buhimschi I. , Garfield RE Role of nitric oxide in obstetrics. Prenat Neonatal Med. 1996 ;1(3):292-329.

33.

Vercelli CA , Aisemberg J. , Billi S. , Wolfson ML , Franchi AM Endocannabinoid system and nitric oxide are involved in the deleterious effects of lipopolysaccharide on murine decidua . Placenta. 2009;30(7):579-584.

34.

Vercelli CA , Aisemberg J. , Billi S. , et al. Anandamide regulates lipopolysaccharide-induced nitric oxide synthesis and tissue damage in the murine uterus. Reprod Biomed Online. 2009; 18(6):824-831.

35.

Chang YH , Lee ST , Lin WW Effects of cannabinoids on LPS-stimulated inflammatory mediator release from macrophages: involvement of eicosanoids. J Cell Biochem . 2001; 81(4):715-723.