An Alternative to Naloxone for Rescuing Opioid‐Induced Respiratory Depression by Systemic Fentanyl in Opioid‐Naïve Rats

Abstract

Opioid‐induced respiratory depression (OIRD) underlies opioid lethality. In anesthetized (urethane/chloralose), vagotomized, paralyzed, and artificially ventilated rats, phrenic nerve activity (PNA) was recorded and responses to intravenous (i.v.) fentanyl (FENT), the most lethal opioid, were quantified to assess OIRD. Previously, we reported that FENT silences PNA at a dose of 20 μg/kg, i.v., and that naloxone (1 mg/kg, i.v.), but not vehicle, reverses FENT‐induced PNA arrest. Given evidence that plasma oxytocin (OXTN) rises following systemic naloxone and that OXTN can stimulate cardiorespiratory outputs, we hypothesized that OXTN could partially or fully reverse FENT OIRD. Whereas ongoing PNA burst frequency (0.63 ± 0.09 Hz) was rapidly silenced by FENT, OXTN at doses from 50–100 μg/kg, i.v. (n=4/group) rapidly (0.17 ± 0.09) reinitiated PNA bursting when given 1 min post‐FENT, with burst frequency returning fully to baseline within 1–2 min. FENT also rapidly reduced mean arterial pressure (MAP) (97 ± 7 to 54 ± 11 mmHg), and this effect too was rapidly countered by OXTN, reaching a peak of 169 ± 4 mmHg following the 50 μg/kg dose. To determine if the pressor response to high dose OXTN accounted for rescue of FENT OIRD, pressor responses were elicited post‐FENT with phenylephrine (PE; 8 μg/kg, iv; n=1) and vasopressin (VP; 5 μg/kg, iv; n=2). Although pressor responses to PE (151 mmHg) and VP (162 ± 34 mmHg) were similar to that of OXTN, neither PE nor VP rescued FENT OIRD. We next reduced the OXTN dose to prevent MAP rising above its pre‐FENT baseline. Of doses tested (0.1, 2, 4, 5, 10, 25 μg/kg, i.v.; n=1–4/dose), the lowest OXTN dose able to reverse FENT OIRD (0.86 ± 0.50 min) without an associated pressor response was 5 μg/kg. To exclude OXTN (5 μg/kg, i.v.) rescue reflecting cross‐affinity for VP receptors, the V1a receptor antagonist H‐3186 (4 nmol/kg, i.v.) was given 5 min prior to FENT. H‐3186 neither affected OXTN reversal of FENT OIRD and FENT’s depressor response. The above baseline pressor response to high dose OXTN (50 μg/kg, i.v.), however, was blocked by H‐3186 (n=1). Pretreatment with the OXTN receptor antagonist atosiban (20 μg/kg, i.v.) fully blocked OXTN (5 μg/kg, i.v.) reversal of FENT OIRD, with PNA bursts not returning to baseline for 14 ± 5 min post‐OXTN (n = 2), which is a time to recovery in the absence of intervention. Atosiban also prevented OXTN reversal of FENT’s depressor response (n = 2). These data reveal that activation of OXTN receptors underlies low‐dose OXTN rescue of depressor and PNA arresting effects of FENT. Pressor effects of high dose‐OXTN that cause MAP to overshoot baseline reflect cross‐activation of VP V1a receptors. Findings suggest that circulating OXTN, which increases following systemic naloxone, can reverse FENT‐induced respiratory depression and restore hemodynamic stability in the rat.Support or Funding InformationThis work was supported by American Heart Association Grant 20POST35030003 (ADB) and National Institutes of Health Grant HL088052 (GMT).