Abstract

Prenatal exposure to buprenorphine renders offspring vulnerable to cerebral impairments. In this study, our data demonstrate, for the first time, that prenatal exposure to buprenorphine escalates astrocyte activation concurrent with indications of endoplasmic reticulum (ER) stress in the hippocampi of neonates, and this can be prevented by the coadministration of dextromethorphan with buprenorphine. Furthermore, dextromethorphan can inhibit the accumulation of GPR37 in the hippocampus of newborns caused by buprenorphine and is accompanied by the proapoptotic ER stress response that involves the procaspase-3/CHOP pathway. Primary astrocyte cultures derived from the neonates of the buprenorphine group also displayed aberrant ER calcium mobilization and elevated basal levels of cyclooxygenase-2 (COX-2) at 14 days in vitro while showing sensitivity to lipopolysaccharide-activated expression of COX-2. Similarly, these long-lasting defects in the hippocampus and astrocytes were abolished by dextromethorphan. Our findings suggest that prenatal exposure to buprenorphine might instigate long-lasting effects on hippocampal and astrocytic functions. The beneficial effects of prenatal coadministration of dextromethorphan might be, at least in part, attributed to its properties in attenuating astrocyte activation and hippocampal ER stress in neonates.

Highlights

  • Because a growing number of pregnant opioid users receive buprenorphine maintenance therapy, concerns regarding the adverse effects of this long-lasting opioid on the brain function of offspring have received increasing attention [1,2,3,4]

  • Given the significant roles of astrocytic function in pathophysiological conditions, we propose that dysfunctional astrocytes and associated oxidative and endoplasmic reticulum (ER) stress might contribute to the development of brain dysfunction triggered by the prenatal exposure to opioids

  • To examine whether astrocytes are activated in neonates following prenatal exposure to buprenorphine, immunofluorescent confocal microscopy was performed using an antibody against GFAP for the control and buprenorphine groups

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Summary

Introduction

Because a growing number of pregnant opioid users receive buprenorphine maintenance therapy, concerns regarding the adverse effects of this long-lasting opioid on the brain function of offspring have received increasing attention [1,2,3,4]. In neonatal animal models, offspring with prenatal exposure to buprenorphine have several brain dysfunctions, including demyelination, abnormal cholinergic/dopaminergic development, and decreased neurogenesis; such exposure may increase the death rate in neonates [6,7,8,9]. The mechanisms underlying the adverse effects of prenatal exposure to buprenorphine on the brain function are not fully understood μ-opioid receptor-mediated neurotoxicity in adults has been proposed [10]. Given the significant roles of astrocytic function in pathophysiological conditions, we propose that dysfunctional astrocytes and associated oxidative and endoplasmic reticulum (ER) stress might contribute to the development of brain dysfunction triggered by the prenatal exposure to opioids. Astrocytes become activated with morphological changes and increased expression of glial fibrillary acidic

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