Ontogenetic Oxycodone Exposure Affects Early Life Communicative Behaviors, Sensorimotor Reflexes, and Weight Trajectory in Mice

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.

Sex Differences in Behavioral and Brainstem Transcriptomic Neuroadaptations following Neonatal Opioid Exposure in Outbred Mice

“…Several animal models for NOWS have been developed ( Fodor et al, 2014 ; Chen et al, 2015 ; Byrnes and Vassoler, 2018 ), differing in time of exposure (i.e., prenatally, postnatally, or both), specific opioid (morphine, heroin, methadone, oxycodone, and/or buprenorphine), and dosing regimen (e.g., injections, pellets, mini-pumps; Byrnes and Vassoler, 2018 ; Robinson et al, 2020 ; Minakova et al, 2021 ). The physiological and behavioral consequences of opioids on development depends on the timing, duration, and route of drug administration ( Fodor et al, 2014 ; Byrnes and Vassoler, 2018 ).…”

Alterations of brain microstructures in a mouse model of prenatal opioid exposure detected by diffusion MRI

“…Additionally, significant clusters of diverse microstructural differences were frequently identified in the somatosensory cortex, motor cortex, dorsal striatum, and their respective adjacent white matter. We and others have described delayed development of several sensorimotor-based developmental milestones including the cliff aversion, surface righting, and forelimb grasp task, among others, which suggest opioid exposed offspring may lack the ability to translate multimodal sensory input into complex motor behaviors 21,[63][64][65] . Furthermore, we have also demonstrated that PME disrupts synaptic signaling in the somatosensory cortex, motor cortex and dorsal striatum using brain slice, patch-clamp electrophysiology 21,26,27 .…”

Enhanced heroin analgesic effect in male offspring of sires who self-administered heroin

“…Novel methods to accurately trace the influence of germline modifications through embryogenesis and development will be crucial for advancing the field and developing effective Epidemiological evidence suggests that parental opioid exposure is associated with lower birth weight and adverse developmental outcomes in offsprings (Hunt et al, 2008). Preclinical research found that maternal exposure to opioids from conception through the pup weaning process results in reduced body weight in the offsprings (Minakova et al, 2021). By contrast, other research has indicated that maternal exposure to oxycodone did not affect the birth weight or body weight on postnatal day 8, day 21, and day 30 (Minakova et al, 2022).…”