Abstract 14444: A Novel Role for the Hypothalamic Paraventricular Nucleus in Resuscitation From Opioid-Induced Respiratory Depression by Fentanyl in the Rat

Abstract

Introduction: Opioid receptor antagonists, like naloxone, reverses opioid-induced respiratory depression (OIRD). We recently found that systemic oxytocin reverses fentanyl OIRD in rats. Naloxone triggers a surge in oxytocin release from the hypothalamic paraventricular nucleus (PVN) in anesthetized rats. Hypothesis: Given that naloxone induces PVN oxytocin release, we hypothesized that the PVN, an unrecognized brain region for opioid overdose reversal, is capable of respiratory resuscitation following fentanyl OIRD. Methods: Naloxone (5 mg/kg, i.v.) was given to conscious rats with indwelling venous cannulae. Blood samples were extracted at 5 min post-naloxone to measure plasma oxytocin by ELISA. Under anesthesia, phrenic nerve activity was recorded in vagotomized, paralyzed, and artificially ventilated rats to quantify inspiratory drive following fentanyl (60 nmol/kg, i.v.) and assess OIRD reversal potential following unilateral PVN nanoinjection of naloxone (3 nmol/kg, 50 nL) or vehicle (50 nL). In spontaneously breathing mice with channelrhodopsin expressed exclusively in oxytocin neurons, expired CO 2 was used to monitor rhythmic ventilation and to quantify bradypnea during OIRD. Following fentanyl, blue light (473 nm, 12 mW) pulses (10 ms, 20 Hz) or dummy pulses were delivered to the PVN using a 5 s On/1 s Off pattern for 3 min. Results: Systemic naloxone resulted in a surge in plasma oxytocin compared to vehicle in the conscious rat. Naloxone in PVN both reversed and prevented OIRD by systemic fentanyl in the rat. Photostimulation of PVN oxytocin neurons prevented lethal effects of fentanyl OIRD, whereas dummy pulses failed to prevent lethal respiratory arrest in the mouse. Conclusions: Here, we confirm that naloxone stimulates oxytocin neurons of the PVN and results in a surge of plasma oxytocin. PVN opioid receptor antagonism and photoactivation of PVN oxytocin neurons are individually capable of reversing OIRD. Findings also indicate that PVN oxytocin neurons, previously unrecognized in reversal of OIRD, are a novel target for resuscitation agents.