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 prefentanyl conditions, which could be beneficial in opioid overdose.

Glutathione ethyl ester reverses the deleterious effects of fentanyl on ventilation and arterial blood-gas chemistry while prolonging fentanyl-induced analgesia

“…As such, it would appear that the effects of fentanyl on the processes driving active inspiration in intact rats are of much longer duration than those that occur during passive expiration. Saunders and Levitt 128 provided elegant demonstration that the fentanyl-induced changes in T e and T i occurred in parallel in the in situ arterially-perfused rat brainstem preparation. We therefore presume that sensory inputs or other mechanisms not available in the in situ presentation are responsible for the exaggerated effects on T i as opposed to T e in vivo.…”

Maternal Methadone Destabilizes Neonatal Breathing and Desensitizes Neonates to Opioid-Induced Respiratory Frequency Depression

“…A relatively immature respiratory control system could also explain the increased prevalence of apneas after MM. Lastly, the effects of opioids on other aspects of the respiratory control network could also contribute to these deficits in breathing, including regions influencing pattern and rate (e.g., Kölliker-Fuse, locus coeruleus, and post-inspiratory complex) ( Anderson et al, 2016b ; Kliewer et al, 2019 ; Saunders and Levitt, 2020 ; Varga et al, 2020a , b ). Future studies should focus on identifying the mechanisms of these breathing deficits and involvement of different aspects of the respiratory control circuitry.…”

Neuronal mechanisms underlying opioid-induced respiratory depression: our current understanding

“…Systemic administration of opioids causes reductions in respiratory rate due to small increases in inspiration and large increases in expiration (11,169,210). In the presence of systemic opioid administration, antagonism of MORs (both pre-and postsynaptic receptors) located in the KF/PB at least partially restores respiratory rate, mostly due to reductions in expiratory duration (206,207,211). Antagonism of opioid receptors in the KF/PB also prevents and reverses sustained apnea following systemic fentanyl or remifentanil (206,211).…”