New brainstem targets for counteracting opioid induced apnea

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ABSTRACT While prescription opioids are exceptional analgesics, they have significant side effects, especially opioid- induced persistent apnea (OIPA). A significant public health problem follows from these side effects, as overdoses caused almost 50,000 deaths in 2019, along with non-fatal overdoses that result in costly and often extended hospitalization. The “opioid epidemic” accelerated further during the COVID-19 pandemic, with a 38% increase in deaths due to synthetic opioid overdose (primarily fentanyl) compared to 2019. We propose a logical path to identifying molecules that can block or reverse OIPA that may supplement current treatments, e.g., higher efficacy and safety, longer half-life, possibly preserving opioid-induced analgesia. Opioids depress breathing by actions on two brainstem neural circuits underlying breathing movements, the preBötzinger Complex (preBötC) and the Parabrachial Nuclei (PB), both of which contains neurons expressing µ-opioid receptors (µORs). µORs are inhibitory G-protein coupled receptors (GPCRs) that depress neuronal excitability. Activation of excitatory GPCRs in preBötC and PB can counteract opioid effects on breathing. We propose to sequence the RNA in preBötC and PB neurons that express µORs to determine expression of excitatory GPCRs. Previous studies in awake mice aimed to determine whether preBötC or PB mediates depression of breathing during opioid overdose; however, opioids evoke only a modest decrease in breathing in awake mice, nowhere near an apnea observed in humans during acute opioid intoxication. We therefore propose to determine whether preBötC and/or PB are primarily responsible for OIPA in mice using a methodology in which we consistently evoke a complete apnea following opioid administration. We will select potential target excitatory GPCR receptors, that are coexpressed with µORs in the structure(s) that we find to be primarily responsible for OIPA (preBötC and/or PB). We will then determine the efficacy of the agonists of these GPCRs in counteracting OIPA in anesthetized mice. Success of this exploratory project will generate data for subsequent preclinical and translational investigation of agonists of these receptors as potential therapeutics for reversing OIPA. Prescription opioids are extremely effective painkillers, but overdose can result in death because they also stop breathing. More that 50,000 Americans die each year from opioid overdose. We propose to identify receptors, whose activation can reverse opioids’ effects on breathing.