Inspiratory rhythmogenic activity is burst-independent and opioid-sensitive

How mammalian neural circuits generate rhythmic activity in motor behaviors, such as breathing, walking, and chewing, remains elusive. For breathing, rhythm generation can be localized to a brainstem nucleus called the preBötzinger Complex (preBötC). Rhythmic preBötC population activity consists of small amplitude burstlets, which we hypothesize are rhythmogenic, and larger inspiratory bursts, which drive motoneuronal activity. If burstlets are rhythmogenic, opioids, analgesics that can cause profound respiratory depression, should similarly reduce burstlet frequency. In conditions where burstlets were separated from bursts in medullary slices from neonatal mice, the μ-opioid receptor (μOR) agonist DAMGO decreased burstlet frequency. DAMGO-mediated depression was abolished by genetic deletion of μORs in a glutamatergic preBötC subpopulation and was reduced by Substance P, but not blockade of inhibitory synaptic transmission. Our findings suggest that rhythmogenesis need not rely on strong bursts of activity associated with motor output and point to strategies for ameliorating opioid-induced depression of breathing.