Respiratory depression is the primary cause of death from opioid overdose, yet surprisingly little is known about the mechanisms of opioid-induced respiratory depression. Breathing, like other motor behaviors, is coordinated by a central neuronal network. Studies in the Levitt lab are geared toward understanding how opioids modulate neurons in the brainstem respiratory circuit to cause breathing disturbances. The Kölliker-Fuse (KF) in the dorsolateral pons is an integral component of the respiratory circuit. We have found that opioid-sensitive KF neurons are key mediators of morphine-induced respiratory depression in awake mice. Blockade of mu opioid receptors in the KF area both prevents and reverses fentanyl-induced apnea, and inspiratory KF neurons are silenced by fentanyl, whereas expiratory neurons largely are not affected in pontomedullary network preparations. Recordings from retrograde labeled KF neurons in brain slices have identified that KF neurons that project to the inspiratory controlling areas in the ventrolateral medulla are hyperpolarized by mu opioid agonists and that excitatory projections of KF neurons to the ventrolateral medulla are inhibited by pre-synaptic mu opioid receptors. Ongoing studies are investigating neuromodulator influence on the distributed effect of opioids on the pontomedullary respiratory circuitry.

Rett Syndrome is a neurodevelopmental disorder that occurs due to loss of function mutations in the transcription factor MeCP2, that causes debilitating breathing disturbances, including apneas and irregular breathing. These breathing disturbances are recapitulated in mouse models of Rett Syndrome, which have loss of function mutations in MeCP2. Several neurotransmitter systems are disrupted in Rett Syndrome, but the effect on breathing irregularities is unknown. We have found that a selective 5HT1A agonist F15599 corrects breathing irregularity and reduces apneas in a mouse model of Rett syndrome, without altering locomotor activity. More recently, we found that the dopamine D2 receptor agonist quinpirole significantly reduces apneas and breathing irregularities in Rett Syndrome mice, which may be secondary to homeostatic changes. Current studies are investigating possible mechanisms underlying the breathing abnormalities observed in Rett Syndrome mice using ex vivo brain slice electrophysiology in respiratory-controlling brainstem neurons.