A Holistic Systems Approach to Characterize the Impact of Pre- and Post-natal Oxycodone Exposure on Neurodevelopment and Behavior.

Katherine E Odegaard,Steven J Lisco,Zhiqiu Xia,Alexander R Clark,Chittibabu Guda,Hanjun Wang,Matthew Van Hook,Gurudutt Pendyala,Sneh Koul,Jagadesan Sankarasubramanian,Yutong Liu,Andrew Stothert,Sowmya V Yelamanchili,Melissa Mellon,Victoria L Schaal,Mariano Uberti

doi:10.3389/fcell.2020.619199

Katherine E Odegaard, Steven J Lisco + Show 14 more

Open Access

https://doi.org/10.3389/fcell.2020.619199

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Abstract

Background: Increased risk of oxycodone (oxy) dependency during pregnancy has been associated with altered behaviors and cognitive deficits in exposed offspring. However, a significant knowledge gap remains regarding the effect of in utero and postnatal exposure on neurodevelopment and subsequent behavioral outcomes.Methods: Using a preclinical rodent model that mimics oxy exposure in utero (IUO) and postnatally (PNO), we employed an integrative holistic systems biology approach encompassing proton magnetic resonance spectroscopy (1H-MRS), electrophysiology, RNA-sequencing, and Von Frey pain testing to elucidate molecular and behavioral changes in the exposed offspring during early neurodevelopment as well as adulthood.Results: 1H-MRS studies revealed significant changes in key brain metabolites in the exposed offspring that were corroborated with changes in synaptic currents. Transcriptomic analysis employing RNA-sequencing identified alterations in the expression of pivotal genes associated with synaptic transmission, neurodevelopment, mood disorders, and addiction in the treatment groups. Furthermore, Von Frey analysis revealed lower pain thresholds in both exposed groups.Conclusions: Given the increased use of opiates, understanding the persistent developmental effects of these drugs on children will delineate potential risks associated with opiate use beyond the direct effects in pregnant women.

Highlights

Over the last few years, the increasing trend in opioid abuse has become a major public health crisis across the globe
The hippocampus and the prefrontal cortex (PFC) are key regions involved in substance abuse disorders and the negative emotional state associated with withdrawal (Koob, 2020); systemic opioid exposure has been shown to attenuate hippocampal afferent-driven activity in the PFC (Giacchino and Henriksen, 1998). We have investigated both regions in this study to identify alterations in either area of the brain during the early developmental period spanning from post-natal day 14 (P14) to postnatal day 17 (P17), which corresponds with peak synaptogenesis (Semple et al, 2013)
It is unknown whether in utero (IUO) or PNO exposure influences the expression levels of these metabolites in the offspring

Summary

Introduction

Over the last few years, the increasing trend in opioid abuse has become a major public health crisis across the globe As a result, this steep increase in abuse of prescription opioids, which include both licit and illicit opioids, has resulted in the opioid epidemic (Volkow and McLellan, 2016). This steep increase in abuse of prescription opioids, which include both licit and illicit opioids, has resulted in the opioid epidemic (Volkow and McLellan, 2016) Whilst this epidemic has traversed different groups in the society, pregnant women are a Impacts of Perinatal Oxycodone Exposure vulnerable group since they are prescribed opioids such as morphine, buprenorphine, and methadone, all of which have been shown to cross the placenta (Gerdin et al, 1990; Nanovskaya et al, 2002, 2008), potentially impacting the developing fetus. A significant knowledge gap remains regarding the effect of in utero and postnatal exposure on neurodevelopment and subsequent behavioral outcomes

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