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 preBötzinger Complex (preB?tC). To unravel the cellular- and network-level consequences of MOR activation in the preBötC, 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 preBötC 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 together to make the normally robust inspiratory-rhythm-generating network particularly prone to collapse when challenged with exogenous opioids.

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

“…6). In experiments, suppression of synaptic output does not appear to occur until DAMGO concentrations are above approximately 50 (Baertsch et al, 2021). Therefore, it is not surprising that DAMGO application did not strongly impact the burstlet fraction before the rhythm was ultimately abolished in Sun et al (2019), due to the higher DAMGO sensitivity of that particular experimental preparation, as indicated by the lower dose needed for rhythm cessation.…”

“…In the preBötC, opioids affect neuronal dynamics by binding to the -opioid receptor ( OR). The exact number of preBötC neurons expressing OR is unclear; however, the number appears to be small, with estimates ranging from 8 − 50% (Bachmutsky et al, 2020;Baertsch et al, 2021;Kallurkar et al, 2021). Additionally, OR 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).…”

Advances in Reversal Strategies of Opioid-induced Respiratory Toxicity

“…3–5,90 Baertsch et al . 5 showed that opioids have a dual mechanism of opioid-induced respiratory depression at the pre-Bötzinger complex within the inspiratory rhythm-generating network (fig. 1).…”

“…The main reason lies within the respiratory neuronal network itself in that, as long as respiratory drive is depressed due to activation of the μ-opioid receptor system, the degree of activity that is being generated by nonopioid stimulants is insufficient to overcome depression of respiratory neurons in, for example, the pre-Bötzinger and parabrachial/Kölliker-Fuse complexes, two small brain areas with high respiratory sensitivity to opioids. [3][4][5]90 Baertsch et al 5 showed that opioids have a dual mechanism of opioid-induced respiratory depression at the pre-Bötzinger complex within the inspiratory rhythm-generating network (fig. 1).…”

“…Activation of the μ-opioid receptors expressed within the respiratory neuronal network of the brainstem causes irregular breathing, followed by periodic breathing and eventually the cessation of rhythmic breathing activity. [1][2][3][4][5] Recent studies show that although μ-opioid receptors are widely expressed within the respiratory network, the pre-Bötzinger complex, the brainstem respiratory rhythm generator, and the Kölliker-Fuse nucleus are two crucial areas in the brainstem for development of opioid-induced respiratory depression but also for reversal or prevention of respiratory depression by naloxone and nonopioid respiratory stimulants (fig. 1).…”