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

Abstract

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- expressing neurons were optogenetically identified and manipulated in transgenic mice in vitro and in vivo. Based on these results, a model of OIRD was developed in silico. We conclude that hyperpolarization of MOR-expressing preBӧtC 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.

Putting the theory into ‘burstlet theory’ with a biophysical model of burstlets and bursts in the respiratory preBötzinger complex

“…Recent experimental results by Baertsch et al, 2021 showed that opioid application locally within the preBötC decreases burst frequency but also increases the burstlet fraction. In the preBötC, opioids affect neuronal dynamics by binding to the μ-opioid receptor (μOR).…”

“…In the preBötC, opioids affect neuronal dynamics by binding to the μ-opioid receptor (μOR). The exact number of preBötC neurons expressing μOR is unclear; however, the number appears to be small, with estimates ranging from 8% to 50% ( Bachmutsky et al, 2020 ; Baertsch et al, 2021 ; Kallurkar et al, 2021 ). Additionally, μOR is likely to be selectively expressed on neurons involved in rhythm generation, given that opioid application in the preBötC primarily impacts burst frequency rather than amplitude ( Sun et al, 2019 ; Baertsch et al, 2021 ).…”

“…The exact number of preBötC neurons expressing μOR is unclear; however, the number appears to be small, with estimates ranging from 8% to 50% ( Bachmutsky et al, 2020 ; Baertsch et al, 2021 ; Kallurkar et al, 2021 ). Additionally, μOR is likely to be selectively expressed on neurons involved in rhythm generation, given that opioid application in the preBötC primarily impacts burst frequency rather than amplitude ( Sun et al, 2019 ; Baertsch et al, 2021 ). Importantly, within the preBötC, opioids ultimately impact network dynamics through two distinct mechanisms: (1) hyperpolarization, presumably via activation of a G protein-gated inwardly rectifying potassium leak (GIRK) current ( Kubo et al, 1993 ; Gray et al, 1999 ; Montandon et al, 2016 ), and (2) decreased excitatory synaptic transmission, presumably via decreased presynaptic release ( Ballanyi et al, 2009 ; Wei and Ramirez, 2019 ; Baertsch et al, 2021 ).…”

“…Comparison of experimental data and the effects of progressive increases in and synaptic block on the ( H ) frequency and ( I ) amplitude of bursts as well as ( J ) the burstlet fractions for the traces shown in ( G ). Figure 6H and J have been adapted from Figure 3C and E from Baertsch et al, 2021 . The effects of DAMGO on burst amplitude were not quantified in Baertsch et al, 2021 .…”

“…Figure 6H and J have been adapted from Figure 3C and E from Baertsch et al, 2021 . The effects of DAMGO on burst amplitude were not quantified in Baertsch et al, 2021 .…”