Abstract
Naltrexone is not recommended during pregnancy. However, sustained-release naltrexone implant use in humans has resulted in cases of inadvertent foetal exposure. Here, we used clinically relevant dosing to examine the effects of maternally administered sustained-release naltrexone on the rat brain by examining offspring at birth and in adulthood. Maternal treatment (naltrexone or placebo implant) started before conception and ceased during gestation, birth or weaning. Morphometry was assessed in offspring at birth and adulthood. Adult offspring were evaluated for differences in locomotor behaviour (basal and morphine-induced, 10 mg/kg, s.c.) and opioid neurochemistry, propensity to self-administer morphine and cue-induced drug-seeking after abstinence. Blood analysis confirmed offspring exposure to naltrexone during gestation, birth and weaning. Naltrexone exposure increased litter size and reduced offspring birth-weight but did not alter brain morphometry. Compared to placebo, basal motor activity of naltrexone-exposed adult offspring was lower, yet they showed enhanced development of psychomotor sensitization to morphine. Developmental naltrexone exposure was associated with resistance to morphine-induced down-regulation of striatal preproenkephalin mRNA expression in adulthood. Adult offspring also exhibited greater operant responding for morphine and, in addition, cue-induced drug-seeking was enhanced. Collectively, these data show pronounced effects of developmental naltrexone exposure, some of which persist into adulthood, highlighting the need for follow up of humans that were exposed to naltrexone in utero.
Highlights
Naltrexone is a non-selective opioid receptor antagonist [1], used clinically for persons wanting to abstain from opiates [2] and/or alcohol [3,4]
Naltrexone and 6, b-naltrexol Levels in Dams and Offspring. In both dams and offspring, free 6,b-naltrexol blood-levels were low with many below the limit of detection (.0.1 ng/mg) and a maximum blood concentration of 0.3 ng/ml found in two maternal samples
Our findings suggest that developmental opioid receptor antagonism may cause pathophysiological changes that contribute to compulsive drugseeking behaviour
Summary
Naltrexone is a non-selective opioid receptor antagonist [1], used clinically for persons wanting to abstain from opiates [2] and/or alcohol [3,4]. 52 women have become pregnant while being treated with an Australian naltrexone implant (GKH, personal communication). Limited data from humans treated with oral or sustained-release naltrexone suggest no major adverse neonatal outcomes with respect to birth-weights, APGAR scores and head circumferences [6,8,9] but long-term follow-up is lacking. Animal studies, primarily in rat, show adverse neonatal outcomes, but involved daily subcutaneous injections given directly to postnatal offspring rather than clinically relevant maternal (i.e. indirect) and sustained naltrexone exposure. The primary objective of this study was to use a rat model of maternal administration involving sustained-release of naltrexone throughout gestation and lactation at a clinically-relevant plasma concentration of ,2–10 ng/ml [7,10] and to determine outcomes in neonates and adult offspring
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