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other·neonatology, pediatrics, addiction medicine, pulmonology, neuroscience·PMC10060555

Maternal opioids age-dependently impair neonatal respiratory control networks

Frontiers in Physiology · 6 authors, 2 centres

AI SUMMARY

POPULATIONNeonatal Sprague-Dawley rats (P0–P5) exposed to maternal methadone in utero from embryonic day 17 (E17) through postnatal day 5 (P5)

INTERVENTIONMaternal methadone hydrochloride (5 mg/kg, subcutaneous, daily from E17 to P5)

COMPARISONMaternal no treatment controls

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AGENT 01 · STRUCTURED SUMMARY

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TL;DR

This study demonstrates that maternal opioid exposure in rats age-dependently impairs neonatal central respiratory control networks, with the most severe deficits occurring immediately after birth. The impairments involve brainstem and spinal cord networks beyond the preBötzinger Complex, and lingering opioids contribute to amplitude deficits while blunted responses to exogenous opioids correlate with reduced mu-opioid receptor expression. These findings provide mechanistic insight into respiratory distress observed in infants with Neonatal Abstinence Syndrome (NAS) and highlight central nervous system origins of breathing instability.

Full summary

705 CHARS

**Background:** Infants exposed to opioids in utero are an increasing clinical population, with approximately 80 infants born daily in the U.S. exposed to maternal opioids. These infants are often diagnosed with Neonatal Abstinence Syndrome (NAS), which includes respiratory distress, apneas, and tachypnea. The etiology of these respiratory deficits remains poorly understood due to confounding factors such as polysubstance use, poor nutrition, and stress. The authors developed a late-gestation rodent model (methadone 5 mg/kg, subcutaneous, daily from E17 to P5) to isolate the direct effects of maternal opioids on neonatal central respiratory networks, independent of early developmental disruption.

PICO

PPOPULATION

Neonatal Sprague-Dawley rats (P0–P5) exposed to maternal methadone in utero from embryonic day 17 (E17) through postnatal day 5 (P5)

IINTERVENTION

Maternal methadone hydrochloride (5 mg/kg, subcutaneous, daily from E17 to P5)

OOUTCOME

Fictive respiratory burst frequency, amplitude, burst-to-burst variability (SD1/SD2) in isolated brainstem-spinal cord and medullary slice preparations; mu-opioid receptor immunoreactivity in preBötzinger Complex

STUDY TYPE

other

SPECIALTY

neonatology

SUMMARISED BY

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FIDELITY CHECK

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ORIGINAL PAPER

PMC10060555

Maternal opioids age-dependently impair neonatal respiratory control networks

Frontiers in Physiology

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ABSTRACT

Infants exposed to opioids in utero are an increasing clinical population and these infants are often diagnosed with Neonatal Abstinence Syndrome (NAS). Infants with NAS have diverse negative health consequences, including respiratory distress. However, many factors contribute to NAS, confounding the ability to understand how maternal opioids directly impact the neonatal respiratory system. Breathing is controlled centrally by respiratory networks in the brainstem and spinal cord, but the impact of maternal opioids on developing perinatal respiratory networks has not been studied. Using progressively more isolated respiratory network circuitry, we tested the hypothesis that maternal opioids directly impair neonatal central respiratory control networks. Fictive respiratory-related motor activity from isolated central respiratory networks was age-dependently impaired in neonates after maternal opioids within more complete respiratory networks (brainstem and spinal cords), but unaffected in more isolated networks (medullary slices containing the preBötzinger Complex). These deficits were due, in part, to lingering opioids within neonatal respiratory control networks immediately after birth and involved lasting impairments to respiratory pattern. Since opioids are routinely given to infants with NAS to curb withdrawal symptoms and our previous work demonstrated acute blunting of opioid-induced respiratory depression in neonatal breathing, we further tested the responses of isolated networks to exogenous opioids. Isolated respiratory control networks also demonstrated age-dependent blunted responses to exogenous opioids that correlated with changes in opioid receptor expression within a primary respiratory rhythm generating region, the preBötzinger Complex. Thus, maternal opioids age-dependently impair neonatal central respiratory control and responses to exogenous opioids, suggesting central respiratory impairments contribute to neonatal breathing destabilization after maternal opioids and likely contribute to respiratory distress in infants with NAS. These studies represent a significant advancement of our understanding of the complex effects of maternal opioids, even late in gestation, contributing to neonatal breathing deficits, necessary first steps in developing novel therapeutics to support breathing in infants with NAS.

CITATION EXPORT

Sarah A. Beyeler, Robyn Naidoo, Nina R. Morrison et al.. Maternal opioids age-dependently impair neonatal respiratory control networks. Frontiers in Physiology. (2023). https://doi.org/10.3389/fphys.2023.1109754

AUTHORS

6 · 2 CENTRES

Sarah A. Beyeler, Robyn Naidoo, Nina R. Morrison, Emilee A. McDonald, David Albarrán, Adrianne G. Huxtable

1 Department of Biology, Institute of Neuroscience, University of Oregon, Eugene, OR, United States
2 Department of Human Physiology, University of Oregon, Eugene, OR, United States