Project Summary/Abstract Substance abuse disorders involving opioids have led to a dramatic increase in overdose deaths in the last decade. Death from opioid overdose is precipitated by the effect of opioids on the central nervous system to suppress ventilation. The standard treatment for opioid overdose is naloxone, a µ-opioid receptor antagonist. However, naloxone is not as effective against potent opioids like fentanyl, driving the need to find alternative treatments to counteract opioid-induced respiratory depression. The carotid body, a peripheral chemoreceptor that senses decreases in oxygen to increase breathing, has been the target of several drugs (doxapram, almitrine, and GAL-021) that stimulate ventilation. Interestingly, these drugs can be effective in reversing opioid-induced respiratory depression, but their use is limited by significant side effects. We propose to test the potential of targeting the carotid body through an ectopic olfactory receptor Olfr78 to counteract ventilatory depression caused by opioids. Olfr78 is expressed highly in the carotid body and mediates sensory signaling. To test the therapeutic potential of this approach, we propose the following aims. First, we will determine the ability of existing Olfr78 agonists to stimulate ventilation and reverse respiratory depression induced by morphine and fentanyl. Next, we will perform a high throughput small molecule screen to identify more potent and specific agonists of Olfr78 and verify their ability to acutely activate Olfr78. Finally, we will test the best Olfr78 agonists from the screen for their ability to stimulate carotid body sensory activity as well as ventilation to counteract opioid-induced respiratory depression.