Recruiting active expiration to overcome opioid-induced persistent 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 engage active expiration, thereby increasing tolerance of opioids. Those molecules may supplement current treatments for OIPA, e.g., higher efficacy and safety, longer half-life, possibly preserving opioid-induced analgesia. Opioids depress breathing by actions on inspiratory rhythm generating regions, the preBötzinger Complex (preBötC), either directly by activating µ-opioid receptors (µORs) in preBötC, or indirectly by inhibiting tonic drive from the Parabrachial Nuclei to preBötC. µORs are inhibitory G-protein coupled receptors (GPCRs) that depress neuronal excitability. Parafacial respiratory group (pF) contains an active expiratory oscillator, which is independent of preBötC, is opioid-insensitive and is silent at rest, but can become active during certain conditions, e.g. exercise, high CO2. When it is active, it is tightly coupled to inspiration. We propose to express excitatory GPCR HM3Dq receptors (designer receptors exclusively activated by designer drugs) in pF and test whether activation of these receptors increases the dose of fentanyl required to produce persistent apnea. We will then sequence the pF neurons to determine expression of endogenous excitatory GPCRs and test the efficacy of the agonists of these GPCRs in increasing the dose of fentanyl required to produce persistent apnea 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 preventing OIPA.