Evaluation of the tocolytic effect of morphine in a mouse model of lipopolysaccharide-induced preterm delivery: the role of nitric oxide.
ABSTRACT This study evaluated the preventive effect of morphine on lipopolysaccharide (LPS)-induced preterm delivery and the contribution of the nitric oxide pathway as a mechanism involved in this process.
Pregnant mice were treated with LPS: (a) single doses of 35, 50 and 75 microg/kg; (b) double doses of 25, 35 and 50 microg/kg with a 3-h interval, on gestational day 15. Each treatment group consisted of 5-10 mice and the main outcome measurements were the incidence and gestational duration after injection of the last LPS dose. Administration of LPS (35 microg/kg, with a 3-h interval) induced the highest incidence of preterm delivery in mice. For investigation of morphine effects on preterm delivery, animals were treated either with a single dose (10 or 20 mg/kg), or with double doses (5 or 10 mg/kg; with a 3-h interval) of morphine, 1h before each LPS injection. To assess the involved mechanism, either naltrexone (5 and 10 mg/kg) or N(omega)-nitro-l-arginine methyl ester (l-NAME, 2-10 mg/kg) was administered 1h before the first morphine administration. Any interaction in the incidence and/or time of preterm delivery was ruled out by other groups which received naltrexone or l-NAME, each alone. Data were analyzed by the Fisher's exact test for determination of preterm delivery incidences and by the one-way analysis of variance, followed by post-test Tukey, for determination of gestational duration.
Although LPS induced premature labor and decreased the delivery time to gestational day 16, morphine treatment significantly decreased the incidence of LPS-induced premature labor by 50% and increased the delivery time to gestational day 17.6. Naltrexone (5 mg/kg) did not influence morphine-induced attenuation of preterm delivery rate and pregnancy duration. Unlike naltrexone, l-NAME (2 mg/kg) increased the rate of preterm delivery to 100% and decreased pregnancy duration to gestational day 16 in morphine-treated mice. In fact, l-NAME significantly attenuated morphine's preventive effect on preterm delivery.
Morphine increases the gestational duration and decreases the preterm delivery rate induced by LPS probably through modulation in NO release. l-NAME, unlike naltrexone, reversed the effect of morphine on preterm delivery, demonstrating the involvement of nitric oxidergic pathway.
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ABSTRACT: This study was done to investigate the effects of opioid and nitrergic systems on depression in an experimental model of cholestasis in mice, since elevated levels of these substances are seen in cholestatic subjects. Bile duct ligated (BDL) and sham-operated mice were forced to swim individually and the immobility time in the last 4minutes of the 6minute test was evaluated to determine the effects of cholestasis on depression. To assess the possible involvement of endogenous opioids and nitric oxide (NO), effective and sub-effective doses of naltrexone an antagonist of opioid receptors, and N-nitro-l-arginine methyl ester (L-NAME) a non-specific NO synthase inhibitor,were administrated acutely and chronically to BDL and Sham-operated mice and then their immobility time was measured in forced swimming test (FST). The immobility time significantly decreased after bile-duct ligation. Naltrexone and L-NAME significantly reversed antidepressant like effect of cholestasis. Co-administration of sub-effective doses of naltrexone and L-NAME also reversed antidepressant effect in FST in chronic administration. But acute drug administration did not reverse the anti-depressant effect of cholestasis. We have shown that elevated levels of endogenous opioids and NO in cholestatic mice induce an anti depressant like effect, causing a reduction in the mice immobility time in FST. And the study also showed the predominant effect of opioid system and NO modulation of that in anti-depressant like effect of cholestasis.European journal of pharmacology 03/2013; · 2.59 Impact Factor
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ABSTRACT: Objectives: Immunologic processes are involved in preterm delivery (PTD). Considering the anti-inflammatory properties of muscimol (GABA(A) agonist), the effect of this drug was evaluated in lipopolysaccharide-induced PTD in mice. Methods: PTD was induced by two intraperitoneal injections of lipopolysaccharide (35 µg/kg; n = 11), on gestational day 15 (d15). Muscimol was administered twice on d14 and twice on d15 (1 h prior to each lipopolysaccharide injection; 0.05, 0.1, 0.2 mg/kg; intraperitoneally; n = 8-12). To assess the involved mechanisms, either bicuculline (GABA(A) antagonist; 0.1 and 1 µg/kg; intraperitoneally; n = 6-7) or N(ω)-nitro-l-arginine methyl ester (l-NAME; non-selective inhibitor of nitric oxide (NO) synthase enzymes; 2 mg/kg; intraperitoneally; n = 6) were administered 1 h before each muscimol administration on d14 and the first dose of muscimol on d15. Maternal plasma and amniotic fluid nitrite + nitrate levels, placental histopathologies and uterine contractions were assessed. Results: Muscimol (0.1 mg/kg) significantly decreased lipopolysaccharide-induced PTD rates from 100 to 50% and delayed delivery time from d16 to d18. Muscimol moderately increased maternal plasma and amniotic fluid nitrite + nitrate concentrations and decreased lipopolysaccharide-induced placental inflammation and surge in nitrite + nitrate levels. Contrary to bicuculline, l-NAME reversed the beneficial effects of muscimol. Muscimol did not affect myometrial contractions. Conclusions: Muscimol inhibits lipopolysaccharide-induced PTD through modulating NO release.The journal of maternal-fetal & neonatal medicine: the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 08/2012; · 1.36 Impact Factor
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ABSTRACT: In this study, we explained that exogenous cannabinoid, Delta(9)-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. Preterm delivery was induced by double dose of 35 microg/kg LPS with 3-hour interval on gestational day (gd) 15. Delta(9)-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(omega)-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. 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. Delta(9)-Tetrahydrocannabinol contributes to the regulation of gestational duration in LPS-induced preterm delivery probably by NO coupling through the CB1 receptor.Reproductive sciences (Thousand Oaks, Calif.) 04/2010; 17(4):391-400. · 2.18 Impact Factor