Oxytocin Receptor Activation: An Alternative to Naloxone for Rescuing Opioid‐Induced Respiratory Depression by Systemic Fentanyl

Abstract

Opioid overdose intervention by naloxone, a high affinity receptor antagonist, reverses opioid-induced respiratory depression (OIRD) and analgesia by displacing opioids. Systemic naloxone stimulates release of the hypothalamic neuropeptide oxytocin (OXTN), which has analgesic properties and participates in cardiorespiratory homeostasis. To test the hypothesis that OXTN can reverse OIRD, we assessed the rescue potential of graded doses (0, 0.1, 2, 5, 10, 50 nmol/kg, i.v., n=5-6/dose) of OXTN to counteract fentanyl (60 nmol/kg, i.v.)-induced depression of neural inspiration indexed by recording phrenic nerve activity (PNA) in anesthetized (urethane/α-chloralose), vagotomized, and artificially ventilated rats. OXTN rescued fentanyl OIRD by reducing fentanyl-induced burst arrest (P=0.0057) and recovery time of burst frequency (P=0.0016) and amplitude (P=0.0025), resulting in parabolic inhibitory dose-response curves.OXTN receptor (OXTNR) antagonism (40 nmol/kg, i.v., n=5) impaired OXTN restoration of PNA post-fentanyl (P=0.0207) and prolonged recovery time of PNA frequency (P=0.0066) and amplitude (P=0.0022). Vasopressin (AVP) receptor 1A (V1aR) antagonism restored the efficacy of high dose OXTN to rescue fentanyl OIRD (P<0.0001, n=4-6/dose), resulting in classic sigmoidal inhibitory dose-response curves, and prevented (P>0.9999) transient hypertension from V1aR cross-activation (P=0.0173). Consistent with this finding, post-fentanyl AVP (5 nmol/kg, i.v., n=5) produced acute hypertension (P=0.0004) and failed to reverse OIRD (PNA arrest P=0.6184, PNA freq. P=0.2369, PNA ampl. P=0.9571). The non-peptide OXTNR agonist WAY-267464 (75 nmol/kg, i.v., n=5), which also has V1aR antagonist properties, quickly reversed fentanyl OIRD (P<0.0001), with rapid recovery to baseline PNA frequency (P=0.0011) and amplitude (P=0.0044) without adverse hemodynamic consequences (P=0.4022). Findings indicate that peptide and non-peptide agonist activation of OXTNR without cross-activation of V1aR rescues fentanyl OIRD.OXTNR agonists could be lifesaving resuscitation agents that enhance rather than interrupt opioid analgesia.