Kölliker-Fuse/Parabrachial complex mu opioid receptors contribute to fentanyl-induced apnea and respiratory rate depression

Abstract

Overdoses caused by the opioid agonist fentanyl have increased exponentially in recent years. Identifying mechanisms to counter progression to fatal respiratory apnea during opioid overdose is desirable, but difficult to study in vivo. The pontine Kölliker-Fuse/Parabrachial complex (KF/PB) provides respiratory drive and contains opioid-sensitive neurons. The contribution of the KF/PB complex to fentanyl-induced apnea was investigated using the in situ arterially perfused preparation of rat. Systemic application of fentanyl resulted in concentration-dependent respiratory disturbances. At low concentrations, respiratory rate slowed and subsequently transitioned to an apneustic-like, 2-phase pattern. Higher concentrations caused prolonged apnea, interrupted by occasional apneustic-like bursts. Application of CTAP, a selective mu opioid receptor antagonist, directly into the KF/PB complex reversed and prevented fentanyl-induced apnea by increasing the frequency of apneustic-like bursting. These results demonstrate that countering opioid effects in the KF/PB complex is sufficient to restore phasic respiratory output at a rate similar to pre-fentanyl conditions, which could be beneficial in opioid overdose.