The Kölliker‐Fuse contains opioid‐sensitive inspiratory neurons and contributes to fentanyl‐induced apnea

Abstract

Opioid overdose deaths have rapidly increased largely due to illicitly manufactured fentanyl. The cause of death from opioid overdose is respiratory depression. Opioid‐induced respiratory depression is characterized by decreases in respiratory rate, chemoreceptor reflexes and impairment of the upper airway. The Kölliker‐Fuse (KF) regulates upper airway coordination and modulates respiratory rate. Opioid agonists in the KF reduce respiratory rate and cause apneusis. The influence of the KF during systemic fentanyl‐induced respiratory depression was investigated using the in situ arterially perfused working heart‐brainstem preparation of rat. Application of fentanyl to the preparation resulted in dose‐dependent slowing of rate, apneusis consisting of low‐amplitude phrenic nerve bursts and loss of post‐inspiratory vagal output, and eventually apnea with occasional low amplitude phrenic bursts. Subsequent application of CTAP, a mu opioid receptor antagonist, directly into the KF increased the frequency of low amplitude phrenic nerve bursting to a rate similar to baseline, with no change in vagal output. A similar pattern emerged with pre‐application of the mu opioid antagonist CTAP into the KF prior to systemic fentanyl administration. In separate experiments, KF neurons were recorded extracellularly before and after fentanyl administration. Inspiratory neurons stopped firing upon fentanyl administration, whereas, expiratory neurons continued to fire in the presence of fentanyl. These results suggest that opioid‐sensitive inspiratory neurons in KF may initiate low amplitude phrenic bursts and reverse fentanyl‐induced apnea.Support or Funding InformationFunded by NIH Grant DA038069.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.