Opioids depress breathing through two small brainstem sites

Bachmutsky, Iris; Wei, Xin; Kish, Eszter; Yackle, Kevin

doi:10.1101/807297

Cited by 13 publications

(20 citation statements)

References 38 publications

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“…Opioids given systemically will act on opioid receptors throughout the nervous system (Kibaly et al, 2019), and μORs are expressed in various brain structures regulating breathing (Gray et al, 1999; Manzke et al, 2003; Phillips et al, 2012; Pokorski and Lahiri, 1981; Prkic et al, 2012; Zhang et al, 2007; Zhang et al, 2011). While depression of breathing is unlikely to be dependent on actions at a single site (Lalley et al, 2014; Montandon and Horner, 2014; Stucke et al, 2015), our data are consistent with compelling in vitro and in vivo evidence that the preBötC is the most sensitive site to μOR agonists and that it is largely responsible for respiratory frequency depression by opioids (Bachmutsky et al, 2019; Ballanyi and Ruangkittisakul, 2009; Janczewski et al, 2002; Montandon and Horner, 2014; Montandon et al, 2011; Varga et al, 2019).…”

Section: Discussionsupporting

confidence: 85%

Opioids modulate an emergent rhythmogenic process to depress breathing

Sun

Pérez

et al. 2019

eLife

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How mammalian neural circuits generate rhythmic activity in motor behaviors, such as breathing, walking, and chewing, remains elusive. For breathing, rhythm generation is localized to a brainstem nucleus, the preBötzinger Complex (preBötC). Rhythmic preBötC population activity consists of strong inspiratory bursts, which drive motoneuronal activity, and weaker burstlets, which we hypothesize reflect an emergent rhythmogenic process. If burstlets underlie inspiratory rhythmogenesis, respiratory depressants, such as opioids, should reduce burstlet frequency. Indeed, in medullary slices from neonatal mice, the μ-opioid receptor (μOR) agonist DAMGO slowed burstlet generation. Genetic deletion of μORs in a glutamatergic preBötC subpopulation abolished opioid-mediated depression, and the neuropeptide Substance P, but not blockade of inhibitory synaptic transmission, reduced opioidergic effects. We conclude that inspiratory rhythmogenesis is an emergent process, modulated by opioids, that does not rely on strong bursts of activity associated with motor output. These findings also point to strategies for ameliorating opioid-induced depression of breathing.

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Section: Discussionsupporting

confidence: 85%

Opioids modulate an emergent rhythmogenic process to depress breathing

Sun

Pérez

et al. 2019

eLife

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“…Frequency was reduced, IBI irregularity was increased, and periodic burst failures became apparent ( Figure 7C). The model network responded similarly to simulated MOR activation with synaptic inhibition blocked ( Figure 7C, D), consistent with experimental observations suggesting that inhibitory mechanisms do not play a significant role in producing OIRD (Bachmutsky et al, 2020, Gray et al, 1999a.These network-level effects of simulated MOR activation were associated with changes in the spiking activity of model neurons that were also consistent with our experimental results. Specifically, changes in spiking activity occurred primarily during the inter-burst interval, due to a preferential suppression of spiking among Oprm1+ vs. Oprm1-intrinsically tonic (T) neurons ( Figure 7E, F), whereas spiking during inspiratory bursts was reduced similarly among Oprm1+ and Oprm1-model neurons ( Figure 7G).…”

Section: Modelling the Functional Consequences Of Prebötc Mor Activatsupporting

confidence: 88%

“…To test the functional role of the modelled Oprm1+ subpopulation, Oprm1+ neurons were removed from the rhythmogenic process by either 1) increasing Iopioid such that spikes were no longer generated by Oprm1+ neurons, or 2) increasing synopioid such that the spikes produced by Oprm1+ neurons were inconsequential for their postsynaptic targets (Supplemental Figure 7). Consistent with the critical role of Oprm1+ neurons for preBötC rhythmogenesis in vitro (Bachmutsky et al, 2020, Gray et al, 1999a, Montandon et al, 2011, Wei and Ramirez, 2019, Mellen et al, 2003, both methods of functionally removing the modelled Oprm1+ subpopulation effectively silenced the network rhythm. It is noteworthy, however, that hyperpolarizing Oprm1+ model neurons vs. blocking their synaptic output had distinct effects on spiking activity generated by the network, reminiscent of the differential effects on network spiking we observed during optogenetic hyperpolarization of Oprm1+ neurons vs. MOR activation (see Figure 4).…”

Section: Modelling the Functional Consequences Of Prebötc Mor Activatsupporting

confidence: 53%

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

Baertsch

Bush²,

Burgraff³

et al. 2021

Preprint

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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.

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“…The understanding of the long-distance pathways affected by opioids is now possible by combining the use of the floxed MOR animals (Weibel et al, 2013) to knockout MORs in select neuronal populations (Varga et al, 2019;Bachmutsky et al, 2019). This approach has been used to increase understanding of the action of opioids that mediate respiratory depression (Varga et al, 2019;Bachmutsky et al, 2019). The regulation of respiration is mediated by multiple nuclei.…”

Section: Downloaded Frommentioning

confidence: 99%

Recent Progress in Opioid Research from an Electrophysiological Perspective

Birdsong¹,

Williams²

2020

Mol Pharmacol

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Electrophysiological approaches provide powerful tools to further our understanding of how different opioids affect signaling through opioid receptors; how opioid receptors modulate circuitry involved in processes such as pain, respiration, addiction, and feeding; and how receptor signaling and circuits are altered by physiologic challenges, such as injury, stress, and chronic opioid treatment. The use of genetic manipulations to alter or remove μ -opioid receptors (MORs) with anatomic and cell type specificity and the ability to activate or inhibit specific circuits through opto- or chemogenetic approaches are being used in combination with electrophysiological, pharmacological, and systems-level physiology experiments to expand our understanding of the beneficial and maladaptive roles of opioids and opioid receptor signaling. New approaches for studying endogenous opioid peptide signaling and release and the dynamics of these systems in response to chronic opioid use, pain, and stress will add another layer to our understanding of the intricacies of opioid modulation of brain circuits. This understanding may lead to new targets or approaches for drug development or treatment regimens that may affect both acute and long-term effects of manipulating the activity of circuits involved in opioid-mediated physiology and behaviors. This review will discuss recent advancements in our understanding of the role of phosphorylation in regulating MOR signaling, as well as our understanding of circuits and signaling pathways mediating physiologic behaviors such as respiratory control, and discuss how electrophysiological tools combined with new technologies have and will continue to advance the field of opioid research. SIGNIFICANCE STATEMENT This review discusses recent advancements in our understanding of μ -opioid receptor (MOR) function and regulation and the role of electrophysiological approaches combined with new technologies in pushing the field of opioid research forward. This covers regulation of MOR at the receptor level, adaptations induced by chronic opioid treatment, sites of action of MOR modulation of specific brain circuits, and the role of the endogenous opioid system in driving physiology and behavior through modulation of these brain circuits.

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Opioids depress breathing through two small brainstem sites

Cited by 13 publications

References 38 publications

Opioids modulate an emergent rhythmogenic process to depress breathing

Opioids modulate an emergent rhythmogenic process to depress breathing

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

Recent Progress in Opioid Research from an Electrophysiological Perspective

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