Defining Opioidergic, Glutamatergic Pontine Respiratory Patterned Neurons

Abstract

Opioid overdose deaths have rapidly increased largely due to illicitly manufactured fentanyl. The main 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. Pharmacological inhibition of the Kölliker‐Fuse (KF) nucleus produces strikingly similar impairments to breathing as opioids, thus warranted investigation. Using the arterially perfused preparation, we have previously found that application of CTAP, a selective mu opioid receptor antagonist, directly into the KF prevents fentanyl induced apnea. Although the KF is sufficient to restore phasic motor output, it did not restore eupneic 3‐phase respiratory patterning. To determine the identity of KF neurons modulated by opioids, we performed extracellular recordings before, during and after fentanyl administration. Respiratory phase was determined by phrenic and vagal motor output. A subpopulation of inspiratory and post‐inspiratory pattered neurons stopped firing upon fentanyl administration, whereas, a variety of respiratory patterned neurons continued to fire in the presence of fentanyl, albeit some with changes in frequency. Although many medullary glutamatergic respiratory populations have been identified, the firing pattern of pontine respiratory modulated glutamatergic neurons remain unknown. In separate experiments, a promoter specific optogenetic approach was used with extracellular recording to identify Ca2+/Calmodulin‐dependent protein kinase II (CaMKIIa) expressing, presumably glutamatergic, neurons. These results suggest that KF neurons are differentially impacted by opioids and during overdose may promote aberrant glutamatergic transmission to downstream respiratory nuclei.Support or Funding InformationThis work was supported by NIH R01 DA047976.