Evaluation of the tocolytic effect of morphine in a mouse model of lipopolysaccharide-induced preterm delivery: The role of nitric oxide

Abstract 

Objectives

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.

Study design

Pregnant mice were treated with LPS: (a) single doses of 35, 50 and 75μg/kg; (b) double doses of 25, 35 and 50μg/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 (35μg/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 20mg/kg), or with double doses (5 or 10mg/kg; with a 3-h interval) of morphine, 1h before each LPS injection. To assess the involved mechanism, either naltrexone (5 and 10mg/kg) or N^ω-nitro-l-arginine methyl ester (l-NAME, 2–10mg/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.

Results

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 (5mg/kg) did not influence morphine-induced attenuation of preterm delivery rate and pregnancy duration. Unlike naltrexone, l-NAME (2mg/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.

Conclusion

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.

Keywords: Morphine, Lipopolysaccharide-induced preterm delivery, Nitric oxide, Naltrexone, Mice