Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network

The analgesic utility of opioid-based drugs is limited by the life-threatening risk of respiratory depression. Opioid-induced respiratory depression (OIRD), mediated by the μ-opioid receptor (MOR), is characterized by a pronounced decrease in the frequency and regularity of the inspiratory rhythm, which originates from the medullary preBӧtzinger Complex (preBӧtC). To unravel the cellular- and network-level consequences of MOR activation in the preBӧtC, MOR- express ing neurons were optogenetically identified and manipulated in transgenic micein vitro andin vivo. Based on these results, a model of OIRD was developedin silico. We conclude that hyperpolarization of MOR-expressing preB ӧtC neurons alone does not phenocopy OIRD. Instead, the effects of MOR activation are twofold: 1) pre-inspiratory spiking is reduced and 2) excitatory synaptic transmission is suppressed, thereby disrupting network-driven rhythmogenesis. These dual mechanisms of opioid action act synergistically to make the normally robust inspiratory rhythm generating network particularly prone to collapse when challenged with exogenous opioids.
Source: eLife - Category: Biomedical Science Tags: Neuroscience Source Type: research