A Novel Rat Model of Sleep Apnea Reveals Increased Sensitivity to Opioid‐Induced Respiratory Depression and an Unexpected Role for Endogenous Opioids

Abstract

Opioid‐induced respiratory depression (OIRD) underlies opioid lethality. Sleep disorders, including sleep apnea (SA), increase OIRD susceptibility, but mechanisms remain unknown. Here, we mimicked blood gas fluctuations of SA by exposing conscious rats to chronic intermittent hypoxia with hypercapnia (CIHHC), which consisted of 10 cycles/h of hypoxia (FiO2 reduced from 21% to 8%) with hypercapnia (FiCO2 increased from ~0% to 8%) for 8 h/day for 1 week. OIRD was first assessed in anesthetized (urethane/chloralose), vagotomized, paralyzed, and artificially ventilated rats and was quantified as reduced burst frequency and/or amplitude of phrenic nerve activity (PNA) to graded systemic doses of fentanyl (0, 2, 20, 50 mg/kg, iv; n=2–6/group), the most lethal clinically‐relevant opioid. Fentanyl dose‐dependently reduced PNA burst frequency, amplitude, and width, and increased the duration of PNA quiescence in control and CIHHC exposed rats. CIHHC caused a significant left‐shift of the fentanyl dose‐PNA burst frequency inhibition curve, suggesting increased OIRD potency of fentanyl in our model of SA. To compare endogenous opioid suppression of respiratory drive, the opioid receptor antagonist naloxone (1 mg/kg, iv) was administered. Naloxone increased PNA burst amplitude (40.4 ± 10.6%, n=3) in CIHHC rats compared to controls (3.8 ± 2.0%, n=3) (P<0.01). Additionally, naloxone increased PNA burst amplitude to a greater extent in CIHHC rats (54.1 ± 11.2%, n=2) than controls (9.1 ± 6.7%, n=3; P<0.01) following a 20 mg/kg dose of iv fentanyl – a dose of fentanyl that alone reduced PNA burst frequency (CIHHC: −97.4 ± 2.9%, n=5; Control: −79.2 ± 22.4%, n=3; P<0.01) for at least 5 min in both groups. These data reveal an underlying endogenous opioid inhibitory tonus in our rat model of SA. To exclude the possibility that increased sensitivity to OIRD in our SA model was related to differential anesthesia‐induced respiratory depression relative to controls, unrestrained conscious rats were instrumented with indwelling venous catheters and radio‐frequency telemetry transmitters to measure subpleural pressure as an index of ventilatory movements. In normoxic controls, vehicle did not change respiratory frequency (−1.7 ± 0.9%, n=2), and a 20 μg/kg dose of fentanyl induced a modest bradypnea (−19.3 ± 12.7%, n=3) not accompanied by apnea/hypopnea. In CIHHC rats, vehicle similarly did not change respiratory frequency (−0.9 ± 0.9%, n=2), but fentanyl caused significant bradypnea (−56.2 ± 13.3%, n=3; P<0.05) as well as apnea/hypopnea. These results are consistent with those in anesthetized rats. Collectively, the present findings indicate that CIHHC increases endogenous opioid inhibitory tonus and respiratory depressant effects of a clinically‐relevant opioid, fentanyl. Our CIHHC model mimics clinical findings of increased sensitivity to OIRD amongst SA patients, and provides a model system to investigate mechanisms of opioid respiratory neuromodulation to improve analgesic safety in SA patients.Support or Funding InformationSupport: NIH T32‐HL007446 (ADB), HL088052 (GMT)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.