Opioids are potent analgesics that are frequently used for perioperative pain control. Their most dangerous side effect is life threatening respiratory depression, which poses a particular risk in young infants. In addition to well-known developmental differences in opioid pharmacokinetics, this susceptibility may also be due to immaturity of the respiratory center. In the perioperative setting, the increased risk for apnea in young infants often results in avoidance of opioids and substitution with less potent non-opioid analgesics, which may lead to a poorly controlled stress response and neurodevelopmental injury. Whenever opioids are used for invasive procedures, young infants require extended postoperative cardiorespiratory monitoring to detect respiratory depression, which has significant economic implications. It is thus of great clinical relevance to elicit the mechanisms f opioid-induced respiratory depression (OIRD) and especially to understand the differences between immature and adult organisms. Previous research has focused on opioid effects on the preBtzinger Complex (preBC), which is an important area of respiratory rhythm generation. Many of these studies, however, employed in vitro preparations, supraclinical concentrations of opioid agonists or methods that did not allow for precise localization of the study drug effect (e.g., microdialysis). Only one set of studies in in vivo adult dogs completely refuted the importance of the preBC and localized the effect of clinically relevant opioid concentrations to the parabrachial nucleus (PBN) in the pons. No in vivo studies have yet been published for immature animals. We have developed a unique decerebrate developmental in vivo rabbit preparation that investigates the effects of clinical opioid concentrations on functionally identifed areas in the brainstem with particular focus on age-dependent differences. The model has preserved physiological reflexes and intact neuronal networks and allows for localized nuclear injections of neurotransmitter and mu-opioid receptor agonists and antagonists, single neuron recordings and concomitant drug injections and for intravenous opioid infusions at clinical dose-rates. Preliminary studies in the preBC and PBN of young and adult rabbits have provided ample data indicating that (a) OIRD at clinical doses is mediated by different areas in young and adult rabbits, (b) the preBC is not the main area for OIRD, and (c) the PBN plays an important role in OIRD. The objective of the proposed study is to define the role of the PBN and its interplay with the preBC in clinical OIRD for young and adult animals. We will establish the degree to which bradypnea from intravenous opioids can be reversed in the PBN. We will determine the contributions of preBC and PBN to respiratory rate control, which are likely responsible for the age-dependent differences in opioid effect. We will further identify the anatomical projections of the PBN and neurotransmitters that stimulate the PBN and can thus antagonize OIRD. The results will allow better definition of the age group at risk for OIRD and will aid the development of specific therapeutic strategies to counteract this serious side effect of opioid analgesics.

Public Health Relevance

Opioids such as morphine provide the strongest and most reliable pain relief and are therefore routinely used for surgery. Their most serious side effect i the depression of breathing, which seems more pronounced in young infants. This study proposes to use a rabbit model to determine which areas of the breathing center in the brainstem are most affected by opioids and to establish if important differences in the opioid effects exist between infants and adults, which may be used to provide safer pain control.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Cole, Alison E
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Medical College of Wisconsin
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Zuperku, Edward J; Stucke, Astrid G; Krolikowski, John G et al. (2018) Inputs to medullary respiratory neurons from a pontine subregion that controls breathing frequency. Respir Physiol Neurobiol :
Zuperku, Edward J; Stucke, Astrid G; Hopp, Francis A et al. (2017) Characteristics of breathing rate control mediated by a subregion within the pontine parabrachial complex. J Neurophysiol 117:1030-1042
Miller, Justin R; Zuperku, Edward J; Stuth, Eckehard A E et al. (2017) A Subregion of the Parabrachial Nucleus Partially Mediates Respiratory Rate Depression from Intravenous Remifentanil in Young and Adult Rabbits. Anesthesiology 127:502-514