A Neuromodulatory System that Links Opioid‐Induced Sedation and Respiratory Depression

The main cause of death from opioid overdose is respiratory depression, mediated by mu-opioid-receptors located in the respiratory brainstem. Opioids also cause sedation, which further reduces respiratory drive through largely unknown mechanisms. The Kölliker-Fuse nucleus (KF) in the pons is highly susceptible to inhibition by opioids and significantly contributes to opioid-induced respiratory rate depression and associated changes in breathing pattern. Taking advantage of cell-type specific retrograde neural tracing, we characterized anatomical projections between the main noradrenergic arousal center of the brain, the locus coeruleus (LC) and the KF, which represent a potential link between arousal/sedation and breathing. Our results show that 30% of noradrenergic LC neurons send projections to the KF. To begin to understand the functional role and to define the neurochemical identity of LC to KF projections, we used whole-cell patch clamp recordings from the KF combined with optogenetic stimulation of LC neurons. Optical stimulation of LC axon terminals induces light-evoked glutamatergic excitatory postsynaptic currents in KF neurons. Pharmacological isolation of LC to KF synapses suggests that this pathway is monosynaptic. The glutamatergic excitatory postsynaptic currents are dependent on vesicular glutamate transporter 2 expression in noradrenergic LC neurons. Additionally, prolonged optical stimulations lead to noradrenergic excitatory postsynaptic currents that are blocked by alpha1 receptor antagonist. Thus, LC may drive KF neuron activity via glutamate and/or noradrenaline release. This direct excitatory drive in the LC-KF circuit is sensitive to opioids, which can directly inhibit KF neuron somas, as well as inhibit neurotransmitter release from presynaptic LC terminals. This work provides exciting evidence for an excitatory pathway between the LC and the KF, that may play an important link between opioid-induced sedation and respiratory depression.