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

2021 ◽  
Author(s):  
Nathan A Baertsch ◽  
Nicholas E Bush ◽  
Nicholas J Burgraff ◽  
Jan-Marino Ramirez
Keyword(s):  
Transgenic Mice ◽  
Synaptic Transmission ◽  
Respiratory Depression ◽  
Opioid Receptor ◽  
In Silico ◽  
Pronounced Decrease ◽  
Life Threatening ◽  
Μ Opioid Receptor

AbstractThe 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 (preBӧtC). 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.

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

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Nathan A Baertsch ◽  
Nicholas E Bush ◽  
Nicholas J Burgraff ◽  
Jan-Marino Ramirez
Keyword(s):  
Transgenic Mice ◽  
Synaptic Transmission ◽  
Respiratory Depression ◽  
Opioid Receptor ◽  
In Silico ◽  
Pronounced Decrease ◽  
Life Threatening ◽  
Μ Opioid Receptor

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.

scholarly journals Dexamethasone-induced selective inhibition of the central μ opioid receptor: functional in vivo and in vitro evidence in rodents

1994 ◽  
Vol 113 (4) ◽  
pp. 1416-1422 ◽  
Author(s):  
S. Pieretti ◽  
A. Giannuario ◽  
M.R. Domenici ◽  
S. Sagratella ◽  
A. Capasso ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Selective Inhibition ◽  
Μ Opioid Receptor

scholarly journals In vivo and in vitro inhibition of human liver cancer progress by downregulation of the μ-opioid receptor and relevant mechanisms

2013 ◽  
Vol 30 (4) ◽  
pp. 1731-1738 ◽  
Author(s):  
JIN LU ◽  
ZEFENG LIU ◽  
LINGLING ZHAO ◽  
HUIMIN TIAN ◽  
XIUHUA LIU ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Opioid Receptor ◽  
Human Liver ◽  
Human Liver Cancer ◽  
Μ Opioid Receptor ◽  
In Vitro Inhibition

In vivo and in vitro evaluation of novel μ-opioid receptor agonist compounds

2015 ◽  
Vol 767 ◽  
pp. 193-200 ◽  
Author(s):  
Yoshiaki Nikaido ◽  
Aya Kurosawa ◽  
Hitomi Saikawa ◽  
Satoshi Kuroiwa ◽  
Chiharu Suzuki ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Receptor Agonist ◽  
In Vitro Evaluation ◽  
Opioid Receptor Agonist ◽  
Μ Opioid Receptor

scholarly journals Analysis of cellular and synaptic mechanisms behind spontaneous cortical activity in vitro: Insights from optimization of spiking neuronal network models

2021 ◽  
Author(s):  
Jugoslava Aćimović ◽  
Tuomo Mäki-Marttunen ◽  
Heidi Teppola ◽  
Marja-Leena Linne
Keyword(s):  
Synaptic Transmission ◽  
In Silico ◽  
Microelectrode Array ◽  
Ex Vivo ◽  
Global Network ◽  
Cortical Networks ◽  
Network Bursts ◽  
Synaptic Mechanisms

Spontaneous network bursts, the intervals of intense network-wide activity interleaved with longer periods of sparse activity, are a hallmark phenomenon observed in cortical networks at postnatal developmental stages. Generation, propagation and termination of network bursts depend on a combination of synaptic, cellular and network mechanisms; however, the interplay between these mechanisms is not fully understood. We study this interplay in silico, using a new data-driven framework for generating spiking neuronal networks fitted to the microelectrode array recordings. We recorded the network bursting activity from rat postnatal cortical networks under several pharmacological conditions. In each condition, the function of specific excitatory and inhibitory synaptic receptors was reduced in order to examine their impact on global network dynamics. The obtained data was used to develop two complementary model fitting protocols for automatic model generation. These protocols allowed us to disentangle systematically the modeled cellular and synaptic mechanisms that affect the observed network bursts. We confirmed that the change in excitatory and inhibitory synaptic transmission in silico, consistent with pharmacological conditions, can account for the changes in network bursts relative to the control data. Reproducing the exact recorded network bursts statistics required adapting both the synaptic transmission and the cellular excitability separately for each pharmacological condition. Our results bring new understanding of the complex interplay between cellular, synaptic and network mechanisms supporting the burst dynamics. While here we focused on analysis of in vitro data, our approach can be applied ex vivo and in vivo given that the appropriate experimental data is available.

scholarly journals Novel Positive Allosteric Modulators of µ Opioid Receptor—Insight from In Silico and In Vivo Studies

2020 ◽  
Vol 21 (22) ◽  
pp. 8463
Author(s):  
Damian Bartuzi ◽  
Ewa Kędzierska ◽  
Agnieszka A. Kaczor ◽  
Helmut Schmidhammer ◽  
Dariusz Matosiuk
Keyword(s):  
Opioid Receptor ◽  
In Silico ◽  
Antinociceptive Effect ◽  
In Vivo Studies ◽  
Allosteric Modulators ◽  
Allosteric Site ◽  
Μ Opioid Receptor ◽  
Dynamics Simulations ◽  
Higher Doses

Opioids are the drugs of choice in severe pain management. Unfortunately, their use involves serious, potentially lethal side effects. Therefore, efforts in opioid drug design turn toward safer and more effective mechanisms, including allosteric modulation. In this study, molecular dynamics simulations in silico and ‘writhing’ tests in vivo were used to characterize potential allosteric mechanism of two previously reported compounds. The results suggest that investigated compounds bind to μ opioid receptor in an allosteric site, augmenting action of morphine at subeffective doses, and exerting antinociceptive effect alone at higher doses. Detailed analysis of in silico calculations suggests that first of the compounds behaves more like allosteric agonist, while the second compound acts mainly as a positive allosteric modulator.

scholarly journals Respiratory depression in rats induced by alcohol and barbiturate and rescue by ampakine CX717

2012 ◽  
Vol 113 (7) ◽  
pp. 1004-1011 ◽  
Author(s):  
Jun Ren ◽  
Xiuqing Ding ◽  
John J. Greer
Keyword(s):  
Respiratory Depression ◽  
Circulatory Support ◽  
Respiratory Drive ◽  
Drug Induced ◽  
Adult Rats ◽  
Respiratory Rhythmogenesis ◽  
Life Threatening ◽  
Preclinical And Clinical Studies

Barbiturate use in conjunction with alcohol can result in severe respiratory depression and overdose deaths. The mechanisms underlying the additive/synergistic actions were unresolved. Current management of ethanol-barbiturate-induced apnea is limited to ventilatory and circulatory support coupled with drug elimination. Based on recent preclinical and clinical studies of opiate-induced respiratory depression, we hypothesized that ampakine compounds may provide a treatment for other types of drug-induced respiratory depression. The actions of alcohol, pentobarbital, bicuculline, and the ampakine CX717, alone and in combination, were measured via 1) ventral root recordings from newborn rat brain stem-spinal cord preparations and 2) plethysmographic recordings from unrestrained newborn and adult rats. We found that ethanol caused a modest suppression of respiratory drive in vitro (50 mM) and in vivo (2 g/kg ip). Pentobarbital induced an ∼50% reduction in respiratory frequency in vitro (50 μM) and in vivo (28 mg/kg for pups and 56 mg/kg for adult rats ip). However, severe life-threatening apnea was induced by the combination of the agents in vitro and in vivo via activation of GABAA receptors, which was exacerbated by hypoxic (8% O2) conditions. Administration of the ampakine CX717 alleviated a significant component of the respiratory depression in vitro (50–150 μM) and in vivo (30 mg/kg ip). Bicuculline also alleviated ethanol-/pentobarbital-induced respiratory depression but caused seizure activity, whereas CX717 did not. These data demonstrated that ethanol and pentobarbital together caused severe respiratory depression, including lethal apnea, via synergistic actions that blunt chemoreceptive responses to hypoxia and hypercapnia and suppress central respiratory rhythmogenesis. The ampakine CX717 markedly reduced the severity of respiratory depression.

scholarly journals Synthesis and Evaluation of Novel Biased μ-Opioid-Receptor (μOR) Agonists

Molecules ◽  
2019 ◽  
Vol 24 (2) ◽  
pp. 259 ◽  
Author(s):  
Mengjun Ma ◽  
Jialin Sun ◽  
Menghua Li ◽  
Zixing Yu ◽  
Jingchao Cheng ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
G Protein Coupled Receptors ◽  
Formalin Injection ◽  
Writhing Test ◽  
Analgesic Effects ◽  
Μ Opioid Receptor ◽  
G Protein Coupled ◽  
Target Side

‘Biased’ ligands of G protein-coupled receptors (GPCRs) represent a type of promising analgesic with reduced on-target side effects. PZM21, a potent μ-opioid-receptor (μOR)-biased agonist with a new chemical scaffold compared to classic opioids, has been identified as a therapeutic lead molecule for treating pain. In the current study, novel PZM21 analogues were synthesized and evaluated for their in vitro and in vivo efficacy. Novel compound 7a and PZM21 demonstrated undetectable β-arrestin-2 recruitment, however, their analgesic effects need to be further confirmed. Compounds 7b, 7d, and 7g were stronger analgesics than PZM21 in both the mouse formalin injection assay and the writhing test. Compound 7d was the most potent analogue, requiring a dose that was 1/16th to 1/4th of that of PZM21 for its analgesic activity in the two assays, respectively. Therefore, compound 7d could serve as a lead to develop new biased μOR agonists for treating pain.

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