Endogenous Opioid Tone in the Hypothalamic Paraventricular Nucleus in an Animal Model of Sleep Apnea: Possible Role in Enhanced Sensitivity to Opioid‐Induced Respiratory Depression

Abstract

Central opioid‐induced respiratory depression (OIRD) can cause fatal respiratory arrest. Clinically, patients with sleep apnea (SA) have a higher incidence of fatal OIRD and rescue from OIRD frequently requires a higher dose of the opioid antagonist naloxone. Mechanisms conferring increased susceptibility to OIRD in SA patients have yet to be investigated. We recently established a preclinical model of SA‐related OIRD hypersensitivity in which adult Sprague‐Dawley rats are exposed for 8 h/day to 10 cycles/h of hypoxia (21% to 8% O2) with hypercapnia (0% to 8% CO2) for 1 week. We found that this chronic intermittent hypoxia with hypercapnia (CIHHC) model significantly enhances inhibition of PNA burst frequency caused by graded doses of the most lethal clinically‐relevant opioid, fentanyl (CIHHC IC50 = 2.0 mg/kg vs. Control IC50 = 11.0 mg/kg). We also discovered an endogenous opioid tonus in CIHHC exposed rats that tonically suppresses their resting respiratory drive. The latter was revealed as a significant increase of PNA burst amplitude following administration of naloxone (1 mg/kg, iv) that was largely absent in normoxic controls (CIHHC: +40.4 ± 10.6% vs. Control: +3.8 ± 2.0%; n=3/group). However, sources of endogenous opioid tonus was not revealed by systemic naloxone. One brain region implicated in SA‐related cardiorespiratory dysfunction is the hypothalamic paraventricular nucleus (PVN). Importantly, PVN neurons have potential both to produce and respond to opioids. To determine whether endogenous opioids within the PVN contribute to respiratory drive in CIHHC rats, naloxone (1 nmol/side) was administered bilaterally and effects on PNA bursting were analyzed. Similar to systemic administration, PVN naloxone increased PNA burst amplitude to a significantly greater extent in CIHHC rats (+20.1 ± 6.8%, n=3) compared to normoxic controls (+4.0 ± 1.9%, n=5) (P<0.05), indicating greater endogenous opioid tonus in the PVN of our rat model of SA. In CIHHC rats, PVN pre‐treatment with naloxone also attenuated OIRD to systemic fentanyl (20 mg/kg, iv), raising the possibility that increased endogenous opioid tone in the PVN could contribute to their increased sensitivity to OIRD. In control rats, PVN naloxone also attenuated, to a lesser extent, systemic fentanyl‐induced OIRD, which was surprising given that it failed to alter the frequency and amplitude of ongoing PNA bursts. The latter suggests that PVN naloxone stabilizes, without overtly driving, the respiratory network, thereby reducing its vulnerability to OIRD. Taken together, our findings indicate that targeting opioid receptors in the PVN has potential to attenuate OIRD and may be especially effective in patients with SA, who are at greater risk.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.