Disruption of Neurorespiratory Control by Acute Inflammation, Neonatal Inflammation, and Perinatal Opioids
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Date
2020-02-27
Authors
Hocker, Austin
Journal Title
Journal ISSN
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Publisher
University of Oregon
Abstract
Adequate respiratory control is vital, but is disrupted by stressors such as inflammation or opioids. Additionally, early-life stressors may have long-lasting consequences for adult breathing, increasing the risk of disease. This dissertation focuses on how acute inflammation impairs adult respiratory control mechanisms and explores the consequences of two early life stressors, neonatal inflammation and perinatal opioids.
Respiratory plasticity is a key feature of respiratory control, commonly studied in the form of phrenic long-term facilitation (LTF), evoked by acute intermittent hypoxia. Two distinct molecular pathways evoke LTF: the Q-pathway which is impaired by low-level inflammation, and the S-pathway which is inflammation-resistant. Chapters II and III further our mechanistic understanding of how inflammation impacts respiratory plasticity.
Chapter II demonstrates spinal activation of the interleukin-1 (IL-1) receptor is necessary for impairing Q-pathway LTF after inflammation. However, IL-1beta, the endogenous ligand of IL-1R, is not sufficient to impair LTF in healthy animals, suggesting other inflammatory signals are required.
While LPS or simulated sleep apnea induces inflammation and impairs Q-pathway-evoked LTF, chapter III demonstrates these impairments are generalizable to viral-mimetic induced inflammation which impairs Q-pathway, but not S-pathway-evoked pLTF.
Chapter IV demonstrates the long-lasting impairment of adult respiratory plasticity following a single bout of LPS-induced early-life inflammation. Early-life inflammation impaired both Q-pathway and S-pathway-evoked LTF in male and female rats. Despite a lack of adult pro-inflammatory gene expression, Q-pathway LTF was restored by adult anti-inflammatory treatment, demonstrating ongoing inflammatory signaling after neonatal inflammation. S-pathway-evoked LTF was revealed by adenosine receptor agonism, suggesting upstream impairment in adenosine release.
Chapter V investigates the impact of maternal opioid use, another common perinatal stressor. Maternal methadone increases neonatal apneas and mitigates acute methadone-induced respiratory depression, demonstrating perinatal opioids destabilize neonatal respiratory control in rats.
These studies demonstrate neurorespiratory control is disrupted by acute inflammation, neonatal inflammation, and perinatal opioids. The research contributes to our fundamental understanding of how inflammation impairs adult respiratory plasticity, both acutely and after a single early-life exposure. Further, it lays the foundation for future studies investigating how perinatal opioids alter the developing respiratory control system. This dissertation includes previously published, coauthored material.
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Keywords
Development, Inflammation, Neuroplasticity, Opioids, Respiratory Physiology