Maternal Methadone Destabilizes Neonatal Breathing and Desensitizes Neonates to Opioid-Induced Respiratory Frequency Depression

16 pagesPregnant women and developing infants are understudied populations in the opioid crisis, despite the rise in opioid use during pregnancy. Maternal opioid use results in diverse negative outcomes for the fetus/newborn, including death; however, the effects of perinatal (maternal and neonatal) opioids on developing respiratory circuitry are not well understood. Given the profound depressive effects of opioids on central respiratory networks controlling breathing, we tested the hypothesis that perinatal opioid exposure impairs respiratory neural circuitry, creating breathing instability. Our data demonstrate maternal opioids increase apneas and destabilize neonatal breathing. Maternal opioids also blunted opioid-induced respiratory frequency depression acutely in neonates; a unique finding since adult respiratory circuity does not desensitize to opioids. This desensitization normalized rapidly between postnatal days 1 and 2 (P1 and P2), the same age quantal slowing emerged in respiratory rhythm. These data suggest significant reorganization of respiratory rhythm generating circuits at P1–2, the same time as the preBötzinger Complex (key site of respiratory rhythm generation) becomes the dominant respiratory rhythm generator. Thus, these studies provide critical insight relevant to the normal developmental trajectory of respiratory circuits and suggest changes to mutual coupling between respiratory oscillators, while also highlighting how maternal opioids alter these developing circuits. In conclusion, the results presented demonstrate neurorespiratory disruption by maternal opioids and blunted opioid-induced respiratory frequency depression with neonatal opioids, which will be important for understanding and treating the increasing population of neonates exposed to gestational opioids.Supported by the University of Oregon (AHu)

IL-1 receptor activation undermines respiratory motor plasticity after systemic inflammation

Inflammation undermines respiratory motor plasticity, yet we are just beginning to understand the inflammatory signaling involved. Because interleukin-1 (IL-1) signaling promotes or inhibits plasticity in other central nervous system regions, we tested the following hypotheses: 1) IL-1 receptor (IL-1R) activation after systemic inflammation is necessary to undermine phrenic long-term facilitation (pLTF), a model of respiratory motor plasticity induced by acute intermittent hypoxia (AIH), and 2) spinal IL-1β is sufficient to undermine pLTF. pLTF is significantly reduced 24 h after lipopolysaccharide (LPS; 100 μg/kg ip, 12 ± 18%, n = 5) compared with control (57 ± 25%, n = 6) and restored by peripheral IL-1R antagonism (63 ± 13%, n = 5, AF-12198, 0.5 mg/kg ip, 24 h). Furthermore, acute, spinal IL-1R antagonism (1 mM AF-12198, 15 μl it) restored pLTF (53 ± 15%, n = 4) compared with LPS-treated rats (11 ± 10%; n = 5), demonstrating IL-1R activation is necessary to undermine pLTF after systemic inflammation. However, in healthy animals, pLTF persisted after spinal, exogenous recombinant rat IL-1β (rIL-1β) (1 ng ± AIH; 66 ± 26%, n = 3, 10 ng ± AIH; 102 ± 49%, n = 4, 100 ng + AIH; 93 ± 51%, n = 3, 300 ng ± AIH; 37 ± 40%, n = 3; P &lt; 0.05 from baseline). In the absence of AIH, spinal rIL-1β induced progressive, dose-dependent phrenic amplitude facilitation (1 ng; −3 ± 5%, n = 3, 10 ng; 8 ± 22%, n = 3, 100 ng; 31 ± 12%, P &lt; 0.05, n = 4, 300 ng; 51 ± 17%, P &lt; 0.01 from baseline, n = 4). In sum, IL-1R activation, both systemically and spinally, undermines pLTF after LPS-induced systemic inflammation, but IL-1R activation is not sufficient to abolish plasticity. Understanding the inflammatory signaling inhibiting respiratory plasticity is crucial to developing treatment strategies utilizing respiratory plasticity to promote breathing during ventilatory control disorders.NEW &amp; NOTEWORTHY This study gives novel insights concerning mechanisms by which systemic inflammation undermines respiratory motor plasticity. We demonstrate that interleukin-1 signaling, both peripherally and centrally, undermines respiratory motor plasticity. However, acute, exogenous interleukin-1 signaling is not sufficient to undermine respiratory motor plasticity.</jats:p

Maternal Methadone Destabilizes Neonatal Breathing and Desensitizes Neonates to Opioid-Induced Respiratory Frequency Depression

Pregnant women and developing infants are understudied populations in the opioid crisis, despite the rise in opioid use during pregnancy. Maternal opioid use results in diverse negative outcomes for the fetus/newborn, including death; however, the effects of perinatal (maternal and neonatal) opioids on developing respiratory circuitry are not well understood. Given the profound depressive effects of opioids on central respiratory networks controlling breathing, we tested the hypothesis that perinatal opioid exposure impairs respiratory neural circuitry, creating breathing instability. Our data demonstrate maternal opioids increase apneas and destabilize neonatal breathing. Maternal opioids also blunted opioid-induced respiratory frequency depression acutely in neonates; a unique finding since adult respiratory circuity does not desensitize to opioids. This desensitization normalized rapidly between postnatal days 1 and 2 (P1 and P2), the same age quantal slowing emerged in respiratory rhythm. These data suggest significant reorganization of respiratory rhythm generating circuits at P1–2, the same time as the preBötzinger Complex (key site of respiratory rhythm generation) becomes the dominant respiratory rhythm generator. Thus, these studies provide critical insight relevant to the normal developmental trajectory of respiratory circuits and suggest changes to mutual coupling between respiratory oscillators, while also highlighting how maternal opioids alter these developing circuits. In conclusion, the results presented demonstrate neurorespiratory disruption by maternal opioids and blunted opioid-induced respiratory frequency depression with neonatal opioids, which will be important for understanding and treating the increasing population of neonates exposed to gestational opioids.</jats:p