Project Grant R01DA060239

OXYTOCIN NEUROTRANSMISSION OVERCOMES SLEEP APNEA-RELATED OIRD HYPERSENSITIVITY - THIS PROPOSAL SEEKS TO UNCOVER THE BIOLOGICAL BASIS FOR WHY SLEEP APNEA PATIENTS ARE MORE SENSITIVE TO OPIOID- INDUCED RESPIRATORY DEPRESSION (OIRD) - THE PRIMARY CAUSE OF DEATH DUE TO OPIOID OVERDOSE. CLINICALLY, THERE IS A PRESSING NEED FOR NEW THERAPEUTICS TO COUNTER RESPIRATORY DEPRESSIVE EFFECTS OF OPIOIDS WITHOUT INTERRUPTING THEIR PAIN-KILLING ACTIONS AND WITHOUT CAUSING UNWANTED WITHDRAWAL EFFECTS. WE RECENTLY DISCOVERED THAT OXYTOCIN, AN ANALGESIC AND ANXIOLYTIC HORMONE AND NEUROTRANSMITTER PRODUCED IN A MAJOR APNEA-SENSITIVE RESPIRATORY AROUSAL HUB, THE PARAVENTRICULAR NUCLEUS OF THE HYPOTHALAMUS (PVH), CAN PREVENT AND REVERSE OIRD BY THE MOST LETHAL OPIOID FENTANYL. NOTABLY, OPIOID RECEPTOR BLOCKADE WITH NARCAN (NALOXONE, NLX) AND INTRANASAL OXYTOCIN BOTH IMPROVE SYMPTOMS OF OBSTRUCTIVE SLEEP APNEA. OUR CONCEPT IS THAT SLEEP APNEA PATIENTS HAVE DEFICIENT OXYTOCIN NEUROTRANSMISSION CAUSED BY AN EXCESS OF ENDOGENOUS OPIOIDS. THIS WOULD EXPLAIN WHY BOTH BLOCKING OPIOID RECEPTORS AND SUPPLEMENTING OXYTOCIN IMPROVE SLEEP APNEA SYMPTOMS. OUR CENTRAL HYPOTHESIS IS THAT DEFICIENT OXYTOCIN NEUROTRANSMISSION FROM THE PVH TO RESPIRATORY NEURONS LEAVES THE RESPIRATORY NETWORK UNABLE TO MOUNT A SUFFICIENT VENTILATORY DEFENSE RESPONSE TO EFFECTIVELY COMBAT OIRD. THIS OXYTOCIN DEFICIENCY IS MODELED AS AN ADAPTIVE RESPONSE TO SLEEP APNEA THAT PREVENTS HYPERVENTILATION THAT WOULD OTHERWISE RESULT FROM TONIC HYPERACTIVITY OF HYPOXIA-SENSITIVE CAROTID BODY CHEMORECEPTORS. TONIC CHEMORECEPTOR ACTIVITY IS A WELL-RECOGNIZED RESPONSE TO SLEEP APNEA THAT CONTRIBUTES TO DEVELOPMENT OF HYPERTENSION. OUR WORKING MODEL HOLDS THAT ADAPTIVE UPREGULATION OF PVH ENDOGENOUS OPIOIDS BY SLEEP APNEA BECOMES MALADAPTIVE WHEN SLEEP APNEA PATIENTS TAKE AN ANALGESIC OR ILLICIT DOSE OF OPIOID, LEADING TO OIRD HYPERSENSITIVITY. ACCORDING TO OUR MODEL, PVH ENDOGENOUS OPIOID UPREGULATION CONSTITUTES HIT #1 IN A DOUBLE- HIT SCENARIO. ADMINISTRATION OF EXOGENOUS OPIOID (I.E., FENTANYL) CONSTITUTES HIT #2, TRIGGERING EXAGGERATED OIRD. SPECIFIC AIMS TEST THE EXTENT TO WHICH EXPERIMENTAL UPREGULATION OF PVH ENDOGENOUS OPIOIDS IS SUFFICIENT IN NORMOXIC MICE TO MIMIC OIRD HYPERSENSITIVITY IN MICE EXPOSED TO OUR CHRONIC INTERMITTENT HYPERCAPNIC HYPOXIA (CIHH) MODEL OF SA. WE WILL ALSO INVESTIGATE MECHANISMS WHEREBY OXYTOCIN RECEPTOR SIGNALING OCCLUDES THE INHIBITOR ACTION OF OPIOIDS ON RESPIRATORY NEURONS WHILE ALSO TESTING WHETHER FENTANYL CIHH OIRD HYPERSENSITIVITY IS NORMALIZED BY PVH OPIOID RECEPTOR BLOCKADE, ELIMINATING HIT #1. STUDIES WILL FURTHER DEFINE THE CONTRIBUTION OF ENDOGENOUS PVH OPIOIDS IN MASKING SLEEP APNEA-RELATED RESPIRATORY HYPERDRIVE AND IN BLUNTED OXYTOCIN EXCITATION OF RESPIRATORY NEURONS. OPTO- AND CHEMOGENETIC EXCITATION AND INHIBITION STUDIES WILL REVEAL THE CAPACITY OF ACUTE AND PROLONGED EXCITATION AND INHIBITION OF PVH OXYTOCIN NEURONS TO PRODUCE EXAGGERATED OIRD IN NORMOXIC MICE AND MITIGATE OIRD HYPERSENSITIVITY IN CIHH MICE. FINDINGS WILL YIELD NEW TRANSLATIONAL INFORMATION ABOUT A POWERFUL OXYTOCINERGIC NEURAL CIRCUIT PREVIOUSLY UNKNOWN TO OPIOID RESUSCITATION RESEARCH AND REVEAL NEW TARGETS TO PREVENT SLEEP APNEA RELATED OIRD HYPERSENSITIVITY.