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Opioid Sensitivity Reveals Two Distinct Rhythmogenic States of the Respiratory Network

Opioid‐induced respiratory depression (OIRD) is a major cause of death that accounts for 68% of all drug overdose mortalities. What makes OIRD particularly dangerous is its unpredictability. Opioid doses leading to OIRD can vary dramatically from individual to individual, and can even vary on a daily basis within the same individual. This striking variability has been a significant barrier for scientists trying to unravel the underlying mechanisms of OIRD, and needs to be considered when trying to develop strategies to prevent or reverse OIRD. To unravel the mechanisms underlying OIRD we used horizontal brainstem slice preparations from mice, that preserve the entire ventral respiratory column which includes the inspiratory rhythmogenic kernel, the PreBötzinger Complex (PreBötC). Importantly, these slices retain variability in sensitivity to opioids reminiscent of variability observed clinically, suggesting locally regulated mechanisms that may contribute to the sensitivity to OIRD. In order to unravel the mechanisms underlying OIRD we manipulated the relative contributions of synaptic conductance and persistent sodium currents (INaP) to rhythm generation and opioid modulation. We attenuated the relative contribution of the INaP current prior to DAMGO (μ‐agonist) administration though the use of either the INaP blockers, Riluzole and 4–9 Anhydrotetrodotoxin (ATTX), and we also used the HCN channel blocker ZD7288. Following administration of these blockers DAMGO sensitivity was increased by 38%, 24%, and 57% respectively. We next altered the network state by lowering [K+]E or by exposing the network to bouts of anoxia. Surprisingly in both conditions (low [K+]E conditions and hypoxic conditions), DAMGO sensitivity was reduced by 100%, indicating that these manipulations rendered respiratory rhythmogenesis insensitive to the effects of OIRD. Since hypoxic gasping is known to depend on INaP current, we tested whether OIRD can be reversed through Na+ current potentiation by administrating the Na+ channel activator, Veratridine. We found that Veratridine administration completely reversed DAMGO‐induced respiratory suppression, suggesting that modulation of INaP dependent mechanisms may be efficacious in reversing OIRD. Taken together, our results suggest that the respiratory rhythm is differentially sensitive to OIRD. Manipulating the relative contributions of synaptic conductance and INaP to rhythmogenesis, leads to significant changes in the sensitivity to opioids. Thus, we hypothesize that the rhythmogenic mechanisms within the isolated respiratory network are not fixed, but may be dynamic allowing the network to operate in two distinct “modes” of rhythm generation: (a) a network state that seems to be driven predominantly through synaptic mechanisms which is sensitive to opioids, and (b) a network state that depends on persistent sodium current (INaP) which is relatively insensitive to opioids. We propose that manipulating the network states of the respiratory network may be a novel strategy to reverse OIRD.