Neural basis of opioid-induced respiratory depression and its rescue

Opioid-induced respiratory depression (OIRD) causes death following an opioid overdose, yet the neurobiological mechanisms of this process are not well understood. Here, we show that neurons within the lateral parabrachial nucleus that express the µ-opioid receptor (PBL neurons) are involved in OIRD pathogenesis. PBL neuronal activity is tightly correlated with respiratory rate, and this correlation is abolished following morphine injection. Chemogenetic inactivation of PBL neurons mimics OIRD in mice, whereas their chemogenetic activation following morphine injection rescues respiratory rhythms to baseline levels. We identified several excitatory G protein-coupled receptors expressed by PBL neurons and show that agonists for these receptors restore breathing rates in mice experiencing OIRD. Thus, PBL neurons are critical for OIRD pathogenesis, providing a promising therapeutic target for treating OIRD in patients.