Targeting a non-opioid signaling pathway to reverse opioid-induced respiratory depression

Project Summary/AbstractThe 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.Project NarrativeDrug overdose is the leading cause of accidental death in the U.S., with opioids being the most
common drug. Existing treatment using naloxone to antagonize the effect of opioids is limited in its efficacy
against potent opioids like fentanyl and carry side effects like opioid withdrawal. We will target a non-opioid
signaling pathway that stimulates breathing to determine its therapeutic potential to reverse opioid-induced
respiratory depression.