Perinatal opioids impair maturation of vital respiratory networks

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PROJECT SUMMARY The number of infants born with Neonatal Abstinence Syndrome (NAS) after maternal opioid exposure is dramatically rising, yet the direct effects of perinatal (maternal + neonatal) opioids on the maturation of neural networks is not well-characterized. Infants diagnosed with NAS exhibit diverse negative outcomes, including respiratory complications that remain poorly understood. Clinically, these infants are treated with exogenous neonatal opioids to curb the withdrawal symptoms, but there is no accepted standard clinical dosing regime and the long-term effects of neonatal opioids treatment remain unclear. The objective of this proposal is to understand the direct effects of maternal and neonatal opioid exposure on the maturation and refinement of vital respiratory control networks maintaining breathing. This project will utilize a novel animal model to inform the development of a clinical standard of care to treat NAS. Unlike other animal models delivering maternal opioids from conception, the proposed model delivers opioids at the onset of respiratory network activity in utero to target the direct effects of opioids on network maturation. Two specific hypotheses will be tested: 1) Maternal opioids cause instability in neonatal breathing by disrupting reciprocal communication between two respiratory networks; 2) Acute, exogenous opioids in neonates after maternal opioids promote pathological maturation of respiratory networks, potentiating neonatal breathing impairments and blunting the response to acute opioids. Our recently published work using this model showed increased apneas (pauses in breathing) and impaired chemoreflexes (responses to respiratory stimuli) in neonates after perinatal opioids. Further, our preliminary data suggest treating NAS infants with acute opioids increase apneic episodes over time, highlighting windows of increased vulnerability for respiratory failure. Our data begin to localize the source of breathing deficits after perinatal opioids, which we hypothesize include impaired maturation of the preBötzinger Complex (fundamental neural network controlling breathing and highly opioid-sensitive) and impaired communication between the preBötzinger Complex and parafacial respiratory group (a second, opioid-insensitive respiratory network), independent of pontine networks. Such insights into mechanisms of impaired breathing in NAS infants are only possible with an innovative, multidisciplinary approach in a rodent model. Our experimental approaches include: in vivo plethysmography assessment of breathing, in vitro neurophysiology allowing direct access to the isolated neural networks controlling breathing, and identification of opioid receptors in respiratory control regions using immunohistochemistry. Results from the proposed studies will significantly advance our understanding of the mechanisms by which perinatal opioids impair maturation of respiratory control networks. These basic science studies are vital to characterizing the direct effects of opioids on maturing neural networks, independent of potential confounding variables such as maternal stress and polysubstance use, and to understanding how to best treat NAS infants – all of which are necessary first steps in developing safe and effective standards of care.