Abstract
Nationwide, opioid misuse among pregnant women has risen four-fold from 1999 to 2014, with commensurate increase in neonates hospitalized for neonatal abstinence syndrome (NAS). NAS occurs when a fetus exposed to opioids in utero goes into rapid withdrawal after birth. NAS treatment via continued post-natal opioid exposure has been suggested to worsen neurodevelopmental outcomes. We developed a novel model to characterize the impact of in utero and prolonged post-natal oxycodone (Oxy) exposure on early behavior and development. Via subcutaneous pump implanted before breeding, C57BL/6J dams were infused with Oxy at 10 mg/kg/day from conception through pup-weaning. At birth, in utero oxy-exposed pups were either cross-fostered (paired with non-Oxy exposed dams) to model opioid abstinence (in utero Oxy) or reared by their biological dams still receiving Oxy to model continued post-natal opioid exposure (prolonged Oxy). Offspring from vehicle-exposed dams served as cross-fostered (in utero Veh) or biologically reared (prolonged Veh) controls. In utero Oxy exposure resulted in sex-dependent weight reductions and altered spectrotemporal features of isolation-induced ultrasonic vocalization (USV). Meanwhile, prolonged Oxy pups exhibited reduced weight and sex-differential delays in righting reflex. Specifically, prolonged Oxy female offspring exhibited increased latency to righting. Prolonged Oxy pups also showed decreases in number of USV calls and changes to spectrotemporal USV features. Overall, ontogenetic Oxy exposure was associated with impaired attainment of gross and sensorimotor milestones, as well as alterations in communication and affective behaviors, indicating a need for therapeutic interventions. The model developed here will enable studies of withdrawal physiology and opioid-mediated mechanisms underlying these neurodevelopmental deficits.
Highlights
In the past two decades, illicit drug use and prescription opioid use in the United States have risen to epidemic proportions, with the United States Department of Health declaring a public health emergency in 2017
Our findings suggest that pups with continued postnatal opioid exposure showed worse overall developmental outcomes compared to pups following opioid cessation at birth, which may have implications regarding the safety of continued opioid treatment as mitigation for clinical neonatal abstinence syndrome (NAS) symptomology
The utilization of a biological dam and cross-foster dam in our novel model of ontogenetic rodent exposure was based on an attempt to parallel opioid exposure through a method most consistent with clinical management and observations
Summary
In the past two decades, illicit drug use and prescription opioid use in the United States have risen to epidemic proportions, with the United States Department of Health declaring a public health emergency in 2017. The United States Department of Health states that 46,802 people died from opioid overdose in 2018 and an estimated 2 million people have an opioid use disorder (ASPA, 2017). The public health crisis is largely driven by increased misuse of the prescription opioids hydrocodone, oxycodone (Oxy), and methadone (Kenan et al, 2012; Haight, 2018). In cases of moderate-severe NAS, neonatal withdrawal is managed by opioid replacement therapy to alleviate withdrawal symptomatology (Wiles et al, 2014). Clinical studies have not addressed whether long-term neurobehavioral outcomes are improved by managing withdrawal or whether continued post-natal exposure to opioids and adjunct agents used for withdrawal management worsen long-term outcomes (Hudak et al, 2012)
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