Modeling Insights into Potential Mechanisms of Opioid-Induced Respiratory Depression within Medullary and Pontine Networks

The opioid epidemic is a pervasive health issue and continues to have a drastic impact on the healthcare system. This is primarily because opioids cause respiratory suppression and can lead to respiratory failure. Opioid administration can affect the frequency and magnitude of inspiratory motor drive by activating µ-opioid receptors, located throughout the respiratory control network in the brainstem. However, the precise neural mechanisms that suppress breathing are not fully understood. Previous research suggests opioids affect medullary and pontine inspiratory neuron activity by disrupting upstream elements within this circuit. One possible target for opioid suppression of inspiratory drive is excitatory synapses. Reduced excitability of these synaptic elements may result in disfacilitation and reduced synchrony among inspiratory neurons. Downstream effects of disfacilitation may result in abnormal output from phrenic motoneurons resulting in distressed breathing. We tested the plausibility of this hypothesis with a computational model of the respiratory network by targeting the synaptic excitability in fictive medullary and pontine populations. Synaptic conductances were systematically decreased while monitoring the overall respiratory motor pattern. Additionally, perturbations of the time constant for persistent sodium currents in simulated conditional burster neurons resulted in different respiratory frequencies when they were embedded into the larger respiratory network. This observation supports the existence of unique regulatory features of large networks that are difficult to predict based on single-cell or small-circuit simulations. These simulations suggest that highly selective, rather than generalized, actions of opioids on synapses within the inspiratory network may account for different observed breathing mechanics.