Neural basis of opioid-induced respiratory depression and its rescue

Abstract

Significance Opioid-induced respiratory depression (OIRD) is the direct cause of death from opioid overdose, which accounts for the current global opioid crisis. Here, we report that neurons expressing the μ-opioid receptors in the lateral parabrachial nucleus of the pontine respiratory group are necessary and sufficient for the pathogenesis of OIRD. Activating these neurons through endogenous or artificial G protein–coupled receptor signaling pathways rescues OIRD in intact mice, suggesting its therapeutic utility in OIRD patients. 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 (PBLOprm1 neurons) are involved in OIRD pathogenesis. PBLOprm1 neuronal activity is tightly correlated with respiratory rate, and this correlation is abolished following morphine injection. Chemogenetic inactivation of PBLOprm1 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 PBLOprm1 neurons and show that agonists for these receptors restore breathing rates in mice experiencing OIRD. Thus, PBLOprm1 neurons are critical for OIRD pathogenesis, providing a promising therapeutic target for treating OIRD in patients.