Neural basis of opioid-induced respiratory depression and its rescue

Liu, Shijia; Kim, Dong-Il; Oh, Tae Gyu; Pao, Gerald M.; Kim, Jong-Hyun; Palmiter, Richard D.; Banghart, Matthew R.; Lee, Kuo‐Fen; Evans, Ronald M.; Han, Sung

doi:10.1101/2020.10.28.359893

Cited by 8 publications

(11 citation statements)

References 59 publications

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“…Most injection sites and implants were larger than most PB subpopulations, which intermingle extensively, so these approaches simultaneously targeted subsets of PB neurons with distinct connections and functions. Now, genetic methods allow investigators to target more specific subpopulations, including an overlapping potpourri of neurons that express Satb2, Calca , Pdyn, Cck , Oxtr1 , Htr2c , Oprm1 , or Tacr1 (Barik et al., 2021; Chiang et al., 2020; Fu et al., 2019; Garfield et al., 2014; Jarvie et al., 2021; Kaur et al., 2017; Liu et al., 2021; Norris et al., 2021; Palmiter, 2018; Park et al., 2020; Ryan et al., 2017; Yang et al., 2020). Limiting the immense potential of this approach were the lack of a framework for understanding ontological relationships between subpopulations and a lack of markers for remaining PB neurons.…”

Section: Discussionmentioning

confidence: 99%

Molecular ontology of the parabrachial nucleus

Karthik

Huang

Delgado

et al. 2022

J of Comparative Neurology

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Diverse neurons in the parabrachial nucleus (PB) communicate with widespread brain regions. Despite evidence linking them to a variety of homeostatic functions, it remains difficult to determine which PB neurons influence which functions because their subpopulations intermingle extensively. An improved framework for identifying these intermingled subpopulations would help advance our understanding of neural circuit functions linked to this region. Here, we present the foundation of a developmental‐genetic ontology that classifies PB neurons based on their intrinsic, molecular features. By combining transcription factor labeling with Cre fate‐mapping, we find that the PB is a blend of two, developmentally distinct macropopulations of glutamatergic neurons. Neurons in the first macropopulation express Lmx1b (and, to a lesser extent, Lmx1a) and are mutually exclusive with those in a second macropopulation, which derive from precursors expressing Atoh1. This second, Atoh1‐derived macropopulation includes many Foxp2‐expressing neurons, but Foxp2 also identifies a subset of Lmx1b‐expressing neurons in the Kölliker–Fuse nucleus (KF) and a population of GABAergic neurons ventrolateral to the PB (“caudal KF”). Immediately ventral to the PB, Phox2b‐expressing glutamatergic neurons (some coexpressing Lmx1b) occupy the KF, supratrigeminal nucleus, and reticular formation. We show that this molecular framework organizes subsidiary patterns of adult gene expression (including Satb2, Calca, Grp, and Pdyn) and predicts output projections to the amygdala (Lmx1b), hypothalamus (Atoh1), and hindbrain (Phox2b/Lmx1b). Using this molecular ontology to organize, interpret, and communicate PB‐related information could accelerate the translation of experimental findings from animal models to human patients.

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Section: Discussionmentioning

confidence: 99%

Molecular ontology of the parabrachial nucleus

Karthik

Huang

Delgado

et al. 2022

J of Comparative Neurology

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“…3) A relatively small number of "expiratory" neurons (<15%, , Harris et al, 2017) that receive more inhibitory input than excitatory input during bursts and only spike during the inter-burst interval; and 4) tonic neurons with spiking that is not modulated by the inspiratory rhythm. To identify the direct targets of MOR activation in the preBötC, we characterized the discharge identities of Oprm1 expressing neurons within the preBötC by crossing an Oprm1 CreGFP mouse line (referred to as Oprm1 Cre for short) (Liu et al, 2021) with Rosa26 lsl-ChR2:EYFP (Rosa26 ChR2 for short) or Rosa26 lsl-ArchT:EYFP (Rosa26ArchT for short) mice. Neonatal Oprm1 Cre ; Rosa26 ChR2 and Oprm1 Cre ; Rosa26 ArchT offspring were used to produce horizontal brainstem slices (Anderson et al, 2016).…”

Section: Phenotypes Of Oprm1+ Prebötc Neuronsmentioning

confidence: 99%

“…Both the beneficial analgesic effects and the detrimental respiratory consequences of opioids are dependent on the Gα i/o -coupled, µ-opioid receptor (MOR) encoded by the Oprm1 gene (Dahan et al, 2001, Sora et al, 1997. Oprm1 is expressed widely throughout the brain (Erbs et al, 2015) (Allen Brain Atlas), and multiple sites in the central and peripheral nervous system are important for modulating the severity of OIRD (Montandon et al, 2011, Kirby and McQueen, 1986, Prkic et al, 2012, Mustapic et al, 2010, Liu et al, 2021. Two brainstem sites important for respiratory controlthe parabrachial nucleus (PBN) and the preBötzinger complex (preBötC) (Varga et al, 2020, Bachmutsky et al, 2020 are particularly important for understanding OIRD, since localized genetic deletions of Oprm1 at these sites abolishes OIRD.…”

Section: Introductionmentioning

confidence: 99%

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

Baertsch

Bush

Burgraff

et al. 2021

eLife

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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 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.

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“…In LC, reducing available surface MORs with a covalent antagonist leads to a reduction not only in the amplitude of MORmediated currents, but also a slowing of activation kinetics (Williams, 2014). To test this hypothesis, we virally overexpressed human MOR (hMOR) with an mCherry tag in Pvalb Cre mice and probed the resulting enhanced MOR signaling with CYLE in TIPP-Psi (Liu et al, 2021)…”

Section: Enkephalin Generates Large Outward Somato-dendritic Currents In Pv-bcs Primarily Through Dors Rather Than Morsmentioning

confidence: 99%

Convergent, functionally independent signaling by mu and delta opioid receptors in hippocampal parvalbumin interneurons

Patel

Weiss

et al. 2021

eLife

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Functional interactions between G protein-coupled receptors are poised to enhance neuronal sensitivity to neuromodulators and therapeutic drugs. Mu and Delta opioid receptors (MORs and DORs) can interact when overexpressed in the same cells, but whether co-expression of endogenous MORs and DORs in neurons leads to functional interactions is unclear. Here, in mice, we show that both MORs and DORs inhibit parvalbumin-expressing basket cells (PV-BCs) in hippocampal CA1 through partially occlusive signaling pathways that terminate on somato-dendritic potassium channels and presynaptic calcium channels. Using photoactivatable opioid neuropeptides, we find that DORs dominate the response to enkephalin in terms of both ligand-sensitivity and kinetics, which may be due to relatively low expression levels of MOR. Opioid-activated potassium channels do not show heterologous desensitization, indicating that MORs and DORs signal independently. In a direct test for heteromeric functional interactions, the DOR antagonist TIPP-Psi does not alter the kinetics or potency of either the potassium channel or synaptic responses to photorelease of the MOR agonist DAMGO. Thus, aside from largely redundant and convergent signaling, MORs and DORs do not functionally interact in PV-BCs in a way that impacts somato-dendritic potassium currents or synaptic transmission. These findings imply that crosstalk between MORs and DORs, either in the form of physical interactions or synergistic intracellular signaling, is not a preordained outcome of co-expression in neurons.

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Neural basis of opioid-induced respiratory depression and its rescue

Cited by 8 publications

References 59 publications

Molecular ontology of the parabrachial nucleus

Molecular ontology of the parabrachial nucleus

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

Convergent, functionally independent signaling by mu and delta opioid receptors in hippocampal parvalbumin interneurons

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