Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms

Opioids depress breathing by inhibition of interconnected respiratory nuclei in the pons and medulla. Mu opioid receptor (MOR) agonists directly hyperpolarize a population of neurons in the dorsolateral pons, particularly the Kolliker-Fuse (KF) nucleus, that are key mediators of opioid-induced respiratory depression. However, the projection target and synaptic connections of MOR-expressing KF neurons are unknown. Here, we used retrograde labeling and brain slice electrophysiology to determine that MOR-expressing KF neurons project to respiratory nuclei in the ventrolateral medulla, including the preBotzinger complex (preBotC) and rostral ventral respiratory group (rVRG). These medullary-projecting, MOR-expressing dorsolateral pontine neurons express FoxP2 and are distinct from calcitonin gene-related peptide-expressing lateral parabrachial neurons. Furthermore, dorsolateral pontine neurons release glutamate onto excitatory preBotC and rVRG neurons via monosynaptic projections, which is inhibited by presynaptic opioid receptors. Surprisingly, the majority of excitatory preBotC and rVRG neurons receiving MOR-sensitive glutamatergic synaptic input from the dorsolateral pons are themselves hyperpolarized by opioids, suggesting a selective opioid-sensitive circuit from the KF to the ventrolateral medulla. Opioids inhibit this excitatory pontomedullary respiratory circuit by three distinct mechanisms-somatodendritic MORs on dorsolateral pontine and ventrolateral medullary neurons and presynaptic MORs on dorsolateral pontine neuron terminals in the ventrolateral medulla-all of which could contribute to opioid-induced respiratory depression.

Automated summary

Opioids inhibit breathing by depressing respiratory nuclei in the pons and medulla. The Kolliker-Fuse (KF) nucleus in the dorsolateral pons, which consists of mu opioid receptor (MOR)-expressing neurons, plays a key role in opioid-induced respiratory depression. MOR-expressing KF neurons project to respiratory nuclei in the ventrolateral medulla, including the preBotzinger complex (preBotC) and rostral ventral respiratory group (rVRG). Glutamatergic projections from dorsolateral pontine neurons to preBotC and rVRG neurons are inhibited by presynaptic opioid receptors. Activation of opioids also hyperpolarizes excitatory preBotC and rVRG neurons, contributing to respiratory depression.