Prenatal exposure to methadone or buprenorphine alters transcriptional networks associated with synaptic signaling in newborn rats

Abstract

While the use of methadone or buprenorphine during pregnancy is beneficial for the mother's health compared to illicit opioid use, prenatal exposure to these medications may have adverse consequences for the unborn child. However, the underlying molecular mechanisms of prenatal opioid exposure on neurodevelopment remain poorly understood. Hence, this study aimed to investigate gene expression changes, focusing on synapse-related genes, in cerebral tissue from newborn rats prenatally exposed to methadone or buprenorphine. Female Sprague-Dawley rats were exposed to methadone (10 mg/kg/day), buprenorphine (1 mg/kg/day), or sterile water through osmotic minipumps during pregnancy. Total RNA was isolated from the cerebrum on postnatal day 2 and analyzed using RNA-sequencing. Analyses of differentially expressed genes (DEGs) and enriched biological processes were conducted to compare the gene expression profiles between treatment groups within each sex. Prenatal buprenorphine exposure resulted in 598 DEGs (333 up- and 265 downregulated) in males and 175 (75 up- and 100 downregulated) in females, while prenatal methadone exposure resulted in 335 DEGs (224 up- and 111 downregulated) in males and 201 (57 up- and 144 downregulated) in females. Gene ontology analyses demonstrated that enriched biological processes included synaptic signaling, immune responses, and apoptosis. Analysis of the DEGs using the synapse database SynGO revealed that males prenatally exposed to buprenorphine displayed the highest number of enriched synapse-related biological process terms. Understanding gene expression changes following prenatal methadone or buprenorphine exposure is crucial to uncover the mechanisms underlying behavioral alterations and to develop interventions to mitigate the impact of opioid exposure on neurodevelopment.