Intermittent hypercapnic hypoxia induces respiratory hypersensitivity to fentanyl accompanied by tonic respiratory depression by endogenous opioids

Allison D. Brackley, Mary Ann Andrade, Glenn M. Toney

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Key points: Sleep apnoea increases susceptibility to opioid-induced respiratory depression (OIRD). Endogenous opioids are implicated as a contributing factor in sleep apnoea. Rats exposed to sleep-phase chronic intermittent hypercapnic hypoxia (CIHH) for 7 days exhibited exaggerated OIRD to systemic fentanyl both while anaesthetized and artificially ventilated and while conscious and breathing spontaneously, implicating heightened CNS inhibitory efficacy of fentanyl. CIHH also induced tonic endogenous opioid suppression of neural inspiration. Sleep-related episodes of hypercapnic hypoxia, as in sleep apnoea, promote hypersensitivity to OIRD, with tonic respiratory depression by endogenous opioids implicated as a potential underlying cause. Abstract: Sleep apnoea (SA) increases opioid-induced respiratory depression (OIRD) and lethality. To test the hypothesis that this results from chronic intermittent bouts of hypercapnic hypoxia (CIHH) accompanying SA, we compared OIRD across continuously normoxic control rats and rats exposed to sleep-phase (8 h/day) CIHH for 1 week. OIRD sensitivity was first assessed in anaesthetized (urethane/α-chloralose), vagotomized and artificially ventilated rats by recording phrenic nerve activity (PNA) to index neural inspiration and quantify PNA burst inhibition to graded doses (0, 2, 20, 50 μg kg-1, i.v.) of the synthetic opioid fentanyl. Fentanyl dose-dependently reduced PNA burst frequency (P = 0.0098–0.0001), while increasing the duration of burst quiescence at 50 μg kg-1 (P < 0.0001, n = 5–6/group/dose). CIHH shifted the fentanyl dose–phrenic burst frequency response curve to the left (P = 0.0163) and increased the duration of burst quiescence (P < 0.0001). During fentanyl recovery, PNA burst width was increased relative to baseline in normoxic and CIHH rats. Systemic naloxone (1 mg kg-1, i.v.) reversed fentanyl-induced PNA arrest in both groups (P = 0.0002), and increased phrenic burst amplitude above baseline (P = 0.0113) in CIHH rats only. Differential sensitivity to anaesthesia as a cause of CIHH-related OIRD hypersensitivity was excluded by observing in conscious spontaneously breathing rats that fentanyl at 20 μg kg-1 (i.v.), which silenced PNA in anaesthetized rats, differentially increased breathing variability in normoxic versus CIHH rats (P = 0.0427), while significantly reducing breathing frequency (P < 0.0001) and periodicity (P = 0.0003) in CIHH rats only. Findings indicate that CIHH increased OIRD sensitivity, with tonic inspiratory depression by endogenous opioids as a likely contributing cause.

Original languageEnglish (US)
Pages (from-to)3239-3257
Number of pages19
JournalJournal of Physiology
Issue number15
StatePublished - Aug 1 2020


  • opioid induced respiratory depression
  • opioids
  • sleep apnoea

ASJC Scopus subject areas

  • Physiology


Dive into the research topics of 'Intermittent hypercapnic hypoxia induces respiratory hypersensitivity to fentanyl accompanied by tonic respiratory depression by endogenous opioids'. Together they form a unique fingerprint.

Cite this