Proposed mechanisms of opioid‐induced respiratory suppression mediated by actions at excitatory synapses within the inspiratory network: Results from a neuromechanical computational model of the respiratory control system

Abstract

Administration of opioids effect the frequency and magnitude of inspiratory motor drive by activating mu-opioid receptors that are located throughout the respiratory control network in the brainstem, specifically in the medulla and pons. The precise neural mechanisms that suppress breathing during opioid use are not fully understood. It is well known that inspiratory neurons within this network, including the pre-BÖtzinger complex, exhibit synchrony with one another, consistent with shared excitation from other neuron populations and/or recurrent mechanisms. One possible target for opioid suppression of inspiratory drive are synapses that drive inspiratory neurons. Reduced excitability of these presynaptic elements would be expected to result in disfacilitation and reduced synchrony among inspiratory neurons. We utilized a computational model of the respiratory network to test the plausibility that reduced synchrony, mediated by decreased conductance of excitatory synapses that drive selected inspiratory neuron populations, and suppresses inspiratory motor drive. Using a stochastic neural network simulator that consisted of discrete “integrate and fire” populations, we simulated an opioid-mediated decrease in the presynaptic excitability by separately reducing conductance at synapses that excite inspiratory driver (I-Driver), inspiratory decrementing (I-Dec), or inspiratory augmenting (I-Aug) neurons. Simulations indicated that decreasing the excitability of recurrent excitatory synapses within the I-Driver neuron population by up to 75% only had a limited depressive effect on the breathing pattern. Decreasing the conductance of the excitatory synaptic population from I-Driver neurons to I-Dec neurons by 50% induced apnea. Reducing the conductance of the recurrent excitatory synapse within the I-Aug neuron population by up to 75% resulted in longer inspiratory phase durations (TI) consistent with that observed during administration of opioids. When the presynaptic conductance of the excitatory synaptic population from I-Driver neurons to I-Aug neurons was reduced, TI decreased and I amplitude increased. Overall, our simulation data support the plausibility of presynaptic effects of opioids on the inspiratory network. Our results also suggest that highly selective, rather than generalized, actions of these drugs on excitatory synapses within the inspiratory network are plausible.