Plausible presynaptic effects of opioids on pontine inspiratory circuits: New insights from a joint neural biomechanical model

Abstract

Administration of opioids significantly effects tidal volume, respiratory rate, and blunts CO2 responsiveness. The precise neural mechanisms that determine the respiratory depressant effects of opioids are controversial. One hypothesis is that mu‐opioid agonists hyperpolarize neurons located in the pons and this action prolongs inspiratory cycle duration. We tested the plausibility of this hypothesis by employing a neuromechanical model of the respiratory control system. We targeted medullary inspiratory neuron axon terminals that influence 4 neuronal populations within the pons that had an inspiratory component to their discharge (inspiratory (I), expiratory/inspiratory (EI), rostral inspiratory/expiratory (rIE), and caudal inspiratory/expiratory (cIE)) neurons). We systematically decreased the conductance of these synapses by 25, 50, 75 and 100 percent and monitored the effect on the respiratory motor pattern. Simulations revealed that decreasing the conductance of synapses from medullary inspiratory neurons to neuronal populations in the pons altered the breathing pattern. In general, a reduction in synaptic conductance from medullary inspiratory neurons to each of the 4 pontine neuron populations decreased their excitability. Decreasing the synaptic conductance from the medullary inspiratory decrementing (I‐Dec) population to the: 1) I pons population resulted in a decrease in phrenic burst frequency and a decrease in the Inspiratory‐Driver (I‐Driver) population excitability, 2) EI pons population resulted in a decrease in I pons excitability and phrenic neurogram magnitude, 3) rIE population did not reveal significant changes in the breathing pattern from control, and 4) cIE population resulted a decrease in I‐Driver population excitability, phrenic neurogram amplitude and phrenic burst frequency. Decreasing conductance of synapses from the inspiratory augmenting (I‐Aug) population to the I pons, cIE, or rIE populations resulted in decreases in phrenic neurogram magnitude. Our simulation data support the plausibility of presynaptic effects of opioids within the pontine respiratory group that induce respiratory depression. Further, these presynaptic effects can induce selective alterations in inspiratory drive and/or breathing cycle timing.