μ-Opioid receptor signalling enhances Kir3 currents in glutamatergic preBötzinger complex neurons in mice

Opioid-induced respiratory depression (OIRD) is mediated, in part, by μ-opioid receptor (μOR) signalling in the respiratory rhythmogenic preBötzinger complex (preBötC). However, it has been unclear whether opioids affect excitatory or inhibitory neurons, which ion channels are modulated, and by what signalling mechanism. This study clarifies these questions. We quantify Oprm1 (μOR gene) expression in preBötC glutamatergic, GABAergic, and glycinergic neurons and show that 67%-77% of each subpopulation express Oprm1 at commensurate levels, suggesting that all preBötC neurons may respond to opioids. We demonstrate that μOR agonist DAMGO increases passive K⁺ conductance in glutamatergic neurons, specifically via membrane-delimited modulation of Kir3 channels. Inhibitory neurons do not respond to DAMGO despite Oprm1 expression. These results suggest that opioid modulation of Kir3 reduces excitability of glutamatergic preBötC neurons, which may contribute to OIRD. We propose that therapies that attenuate membrane-delimited Gβγ signalling may prevent fatal apnoea while circumventing limitations of μOR antagonists like naloxone. KEY POINTS: μ-Opioid receptor activation depresses excitability only in glutamatergic interneurons of the respiratory rhythmogenic preBötzinger complex. Whole-cell and single-channel patch clamp recordings show that μ-opioid receptor agonist DAMGO increases Kir3 conductance by increasing channel activity through a membrane-delimited signalling mechanism. New interventions that reverse opioid-induced respiratory depression could target signalling molecules downstream from the μ-opioid receptor and attenuate Gβγ-Kir3 interactions as an alternative to conventional receptor antagonists.