Maternal opioids age-dependently impair neonatal respiratory control networks.

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.

Impact of inflammation on developing respiratory control networks: rhythm generation, chemoreception and plasticity.

The respiratory control network in the central nervous system undergoes critical developmental events early in life to ensure adequate breathing at birth. There are at least three "critical windows" in development of respiratory control networks: 1) in utero, 2) newborn (postnatal day 0-4 in rodents), and 3) neonatal (P10-13 in rodents, 2-4 months in humans). During these critical windows, developmental processes required for normal maturation of the respiratory control network occur, thereby increasing vulnerability of the network to insults, such as inflammation. Early life inflammation (induced by LPS, chronic intermittent hypoxia, sustained hypoxia, or neonatal maternal separation) acutely impairs respiratory rhythm generation, chemoreception and increases neonatal risk of mortality. These early life impairments are also greater in young males, suggesting sex-specific impairments in respiratory control. Further, neonatal inflammation has a lasting impact on respiratory control by impairing adult respiratory plasticity. This review focuses on how inflammation alters respiratory rhythm generation, chemoreception and plasticity during each of the three critical windows. We also highlight the need for additional mechanistic studies and increased investigation into how glia (such as microglia and astrocytes) play a role in impaired respiratory control after inflammation. Understanding how inflammation during critical windows of development disrupt respiratory control networks is essential for developing better treatments for vulnerable neonates and preventing adult ventilatory control disorders.

One bout of neonatal inflammation impairs adult respiratory motor plasticity in male and female rats.

Neonatal inflammation is common and has lasting consequences for adult health. We investigated the lasting effects of a single bout of neonatal inflammation on adult respiratory control in the form of respiratory motor plasticity induced by acute intermittent hypoxia, which likely compensates and stabilizes breathing during injury or disease and has significant therapeutic potential. Lipopolysaccharide-induced inflammation at postnatal day four induced lasting impairments in two distinct pathways to adult respiratory plasticity in male and female rats. Despite a lack of adult pro-inflammatory gene expression or alterations in glial morphology, one mechanistic pathway to plasticity was restored by acute, adult anti-inflammatory treatment, suggesting ongoing inflammatory signaling after neonatal inflammation. An alternative pathway to plasticity was not restored by anti-inflammatory treatment, but was evoked by exogenous adenosine receptor agonism, suggesting upstream impairment, likely astrocytic-dependent. Thus, the respiratory control network is vulnerable to early-life inflammation, limiting respiratory compensation to adult disease or injury.