Administration of opioids can lead to respiratory depression and eventually death. Opioids can alter the frequency and magnitude of inspiratory motor drive by binding to mu-opioid receptors on inspiratory neurons located in several areas of the brainstem. Lalley (Am J Physiol: Regul. 285:R1287-1304, 2003) suggested that some of the effects of fentanyl on bulbospinal inspiratory neuron activity were presynaptic. We tested the feasibility of pre- vs post-synaptic effects of opioids with an integrate-and-fire computational neural biomechanical model of the brainstem respiratory network. Our previous simulations utilizing this model involved separately reducing conductance at groups of synapses that excited inspiratory-augmenting (I-Aug) or inspiratory-decrementing (I-Dec) neuron populations to simulate opioid-mediated decreases in the presynaptic excitability of excitatory axons to these neurons from inspiratory driver neurons (I-driver). We found that the presynaptic hypothesis was best supported by a mechanism involving depression of the excitatory synapse between I-driver and I-decrementing neurons. The current modeling investigation extends that work by focusing on three inspiratory neuron populations: I-Aug, I-Dec, and late inspiratory (late-I). We separately decreased the conductance of each excitatory synapse to examine how these changes would affect the respiratory pattern. Simulations revealed that systematically decreasing the conductance of synapses from the I-Aug neuron population to late-I and I- Aug bulbospinal populations by 50% resulted in a decrease in frequency, duration, and amplitude of inspiratory drive. Decreasing the conductance of excitatory synapses from I-Dec neurons to I-Aug, and late-I populations had a limited effect on inspiratory activity. Similar results were observed when the conductance of excitatory synapses was reduced from the late-I population to its I-Dec and I-Aug targets. Overall, these results indicate that a plausible mechanism for respiratory suppression by opioids could include depression of excitatory synaptic actions between selected medullary inspiratory neuron populations.
