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