Project Summary/Abstract The opioid epidemic is a growing public health crisis with dramatic increase in overdose deaths caused by potent opioids like fentanyl. Currently, the standard treatment for opioid-induced respiratory depression is naloxone, a µ-opioid receptor antagonist. However, naloxone is less effective against potent synthetic opioids like fentanyl and induces withdrawal in chronic opioid users. To circumvent these problems, we propose to develop ventilatory stimulants that target a non-opioid pathway in the carotid body to reverse opioid-induced respiratory depression. The carotid body is a chemosensory organ that regulates ventilation acutely, and small molecule drugs that activate the carotid body (doxapram, almitrine, and GAL-021) can reverse opioid-induced respiratory depression. However, these drugs act on molecules expressed broadly in many tissues and have significant side effects like panic and cardiac dysrhythmias (doxapram) and peripheral neuropathy (almitrine) that limit their use. We previously identified a G protein-coupled receptor (mouse Olfr78/human OR51E2) that mediates carotid body sensory signaling. Olfr78 is one of the top expressed genes in mouse carotid body sensory cells and the most highly expressed G protein-coupled receptor; OR51E2 is similarly expressed in the human carotid body. Because G protein-coupled receptors make excellent drug targets, we hypothesize that Olfr78/OR51E2 agonists could strongly stimulate CB activity and ventilation with fewer side effects on other tissues. In this proposal, we will identify new Olfr78/OR51E2 agonists to stimulate carotid body sensory activity and ventilation and validate Olfr78/OR51E2 as a target to reverse opioid-induced respiratory depression.