Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network.
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ABSTRACT:
SUBMITTER: Baertsch NA
PROVIDER: S-EPMC8390004 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Unraveling the interplay of excitation and inhibition within rhythm-generating networks remains a fundamental issue in neuroscience. We use a biophysical model to investigate the different roles of local and long-range inhibition in the respiratory network, a key component of which is the pre-Bötzinger complex inspiratory microcircuit. Increasing inhibition within the microcircuit results in a limited number of out-of-phase neurons before rhythmicity and synchrony degenerate. Thus unstructured local inhibition is destabilizing and cannot support the generation of more than one rhythm. A two-phase rhythm requires restructuring the network into two microcircuits coupled by long-range inhibition in the manner of a half-center. In this context, inhibition leads to greater stability of the two out-of-phase rhythms. We support our computational results with in vitro recordings from mouse pre-Bötzinger complex. Partial excitation block leads to increased rhythmic variability, but this recovers after blockade of inhibition. Our results support the idea that local inhibition in the pre-Bötzinger complex is present to allow for descending control of synchrony or robustness to adverse conditions like hypoxia. We conclude that the balance of inhibition and excitation determines the stability of rhythmogenesis, but with opposite roles within and between areas. These different inhibitory roles may apply to a variety of rhythmic behaviors that emerge in widespread pattern-generating circuits of the nervous system.NEW & NOTEWORTHY The roles of inhibition within the pre-Bötzinger complex (preBötC) are a matter of debate. Using a combination of modeling and experiment, we demonstrate that inhibition affects synchrony, period variability, and overall frequency of the preBötC and coupled rhythmogenic networks. This work expands our understanding of ubiquitous motor and cognitive oscillatory networks.
| S-EPMC5626906 | biostudies-other
Project description:We hypothesize that the network topology within the pre-Bötzinger Complex (preBötC), the mammalian respiratory rhythm generating kernel, is not random, but is optimized in the course of ontogeny/phylogeny so that the network produces respiratory rhythm efficiently and robustly. In the present study, we attempted to identify topology of synaptic connections among constituent neurons of the preBötC based on this hypothesis. To do this, we first developed an effective evolutionary algorithm for optimizing network topology of a neuronal network to exhibit a 'desired characteristic'. Using this evolutionary algorithm, we iteratively evolved an in silico preBötC 'model' network with initial random connectivity to a network exhibiting optimized synchronous population bursts. The evolved 'idealized' network was then analyzed to gain insight into: (1) optimal network connectivity among different kinds of neurons-excitatory as well as inhibitory pacemakers, non-pacemakers and tonic neurons-within the preBötC, and (2) possible functional roles of inhibitory neurons within the preBötC in rhythm generation. Obtained results indicate that (1) synaptic distribution within excitatory subnetwork of the evolved model network illustrates skewed/heavy-tailed degree distribution, and (2) inhibitory subnetwork influences excitatory subnetwork primarily through non-tonic pacemaker inhibitory neurons. Further, since small-world (SW) network is generally associated with network synchronization phenomena and is suggested as a possible network structure within the preBötC, we compared the performance of SW network with that of the evolved model network. Results show that evolved network is better than SW network at exhibiting synchronous bursts.
| S-EPMC4859517 | biostudies-literature
Project description:In the U.S., opioid prescription for treatment of pain nearly quadrupled from 1999 to 2014. The diversion and misuse of prescription opioids along with increased use of drugs like heroin and fentanyl, has led to an epidemic in addiction and overdose deaths. The most common cause of opioid overdose and death is opioid-induced respiratory depression (OIRD), a life-threatening depression in respiratory rate thought to be caused by stimulation of opioid receptors in the inspiratory-generating regions of the brain. Studies in mice have revealed that variation in opiate lethality is associated with strain differences, suggesting that sensitivity to OIRD is genetically determined. We first tested the hypothesis that genetic variation in inbred strains of mice influences the innate variability in opioid-induced responses in respiratory depression, recovery time and survival time. Using the founders of the advanced, high-diversity mouse population, the Diversity Outbred (DO), we found substantial sex and genetic effects on respiratory sensitivity and opiate lethality. We used DO mice treated with morphine to map quantitative trait loci for respiratory depression, recovery time and survival time. Trait mapping and integrative functional genomic analysis in GeneWeaver has allowed us to implicate Galnt11, an N-acetylgalactosaminyltransferase, as a gene that regulates OIRD.
| S-EPMC7486296 | biostudies-literature
Project description:Strong opioid analgesics are the mainstay of therapy for the relief of moderate to severe acute nociceptive pain that may occur post-operatively or following major trauma, as well as for the management of chronic cancer-related pain. Opioid-related adverse effects include nausea and vomiting, sedation, respiratory depression, constipation, tolerance, and addiction/abuse liability. Of these, respiratory depression is of the most concern to clinicians owing to the potential for fatal consequences. In the broader community, opioid overdose due to either prescription or illicit opioids or co-administration with central nervous system depressants may evoke respiratory depression. To address this problem, there is ongoing interest in the identification of non-opioid respiratory stimulants to reverse opioid-induced respiratory depression but without reversing opioid analgesia. Promising compound classes evaluated to date include those that act on a diverse array of receptors including 5-hydroxytryptamine, D 1-dopamine, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA) receptor antagonists, and nicotinic acetylcholine as well as phosphodiesterase inhibitors and molecules that act on potassium channels on oxygen-sensing cells in the carotid body. The aim of this article is to review recent advances in the development potential of these compounds for countering opioid-induced respiratory depression.
| S-EPMC7008602 | biostudies-literature
Project description:Opioid-induced respiratory depression (OIRD) causes death following an opioid overdose, yet the neurobiological mechanisms of this process are not well understood. Here, we show that neurons within the lateral parabrachial nucleus that express the µ-opioid receptor (PBL Oprm1 neurons) are involved in OIRD pathogenesis. PBL Oprm1 neuronal activity is tightly correlated with respiratory rate, and this correlation is abolished following morphine injection. Chemogenetic inactivation of PBL Oprm1 neurons mimics OIRD in mice, whereas their chemogenetic activation following morphine injection rescues respiratory rhythms to baseline levels. We identified several excitatory G protein-coupled receptors expressed by PBL Oprm1 neurons and show that agonists for these receptors restore breathing rates in mice experiencing OIRD. Thus, PBL Oprm1 neurons are critical for OIRD pathogenesis, providing a promising therapeutic target for treating OIRD in patients.
| S-EPMC8201770 | biostudies-literature
Project description:Astrocytes are implicated in modulation of neuronal excitability and synaptic function, but it remains unknown if these glial cells can directly control activities of motor circuits to influence complex behaviors in vivo. This study focused on the vital respiratory rhythm-generating circuits of the preBötzinger complex (preBötC) and determined how compromised function of local astrocytes affects breathing in conscious experimental animals (rats). Vesicular release mechanisms in astrocytes were disrupted by virally driven expression of either the dominant-negative SNARE protein or light chain of tetanus toxin. We show that blockade of vesicular release in preBötC astrocytes reduces the resting breathing rate and frequency of periodic sighs, decreases rhythm variability, impairs respiratory responses to hypoxia and hypercapnia, and dramatically reduces the exercise capacity. These findings indicate that astrocytes modulate the activity of CNS circuits generating the respiratory rhythm, critically contribute to adaptive respiratory responses in conditions of increased metabolic demand and determine the exercise capacity.
| S-EPMC5785528 | biostudies-literature
Project description:Background: Respiratory depression is a clinically and economically important but preventable complication of opioids. Genetic factors can help identify patients with high risk for respiratory depression. Methods: In this prospective genotype blinded clinical study, we evaluated the effect of a panel of variants in candidate genes on opioid-related respiratory depression in 347 children following tonsillectomy. Results: Using unsupervised hierarchical clustering and a combination of candidate genotypes and clinical variables, we identified several distinct clusters of patients at high risk (36-38%) and low risk (10-17%) of respiratory depression; the relative risk of respiratory depression for high versus low risk clusters was 2.1-3.8 (p = 0.003). Conclusion: Genetic risk predictions (genetic signatures) along with clinical risk factors effectively identify children at higher and lower risks of opioid-induced respiratory depression. Genetic signatures of respiratory depression offer strategies for improved clinical decision support to guide clinicians to balance the risks of opioid adverse effects with analgesia. Original submitted 9 July 2014; Revision submitted 19 September 2014.
| S-EPMC4287371 | biostudies-literature
Project description:BackgroundSafe postoperative pain relief with opioids is an unmet critical medical need in children. There is a lack of objective, noninvasive bedside tool to assess central nervous system (CNS) effects of intraoperative opioids. Proactive identification of children at risk for postoperative respiratory depression (RD) will help tailor analgesic therapy and significantly improve the safety of opioids in children. Quantitative pupillometry (QP) is a noninvasive, objective, and real-time tool for monitoring CNS effect-time relationship of opioids. This exploratory study aimed to determine the association of QP measures with postoperative RD, as well as to identify the best intraoperative QP measures predictive of postoperative RD in children.MethodsAfter approval from the institutional review board and informed parental consent, in this prospective, observational study of 220 children undergoing tonsillectomy, QP measures were collected at 5 time points: awake preoperative baseline before anesthesia induction (at the time of enrollment [T1]), immediately after anesthesia induction before morphine administration (T2), 3 minutes after intraoperative morphine administration (T3), at the end of surgery (T4), and postoperatively when awake in postanesthesia recovery unit (PACU) (T5). Intraoperative use of opioid and incidence of postoperative RD were collected. Analyses were aimed at exploring correlations of QP measures with the incidence of RD and, if found significant, to develop a predictive model for postoperative RD.ResultsPerioperative QP measures of percentage pupil constriction (CONQ, P = .027), minimum pupillary diameter (MIN, P = .027), and maximum pupillary diameter (MAX, P = .034) differed significantly among children with and without postoperative RD. A predictive model including the minimum pupillary diameter 3 minutes after morphine administration (MIN3), minimum pupillary diameter normalized to baseline (MIN31), and percentage pupillary constriction after surgery (T4) standardized to baseline (T1) (CONQ41), along with the weight-based morphine dose performed the best to predict postoperative RD in children (area under the curve [AUC], 0.76).ConclusionsA model based on pre- and intraoperative pupillometry measures including CONQ, MIN, along with weight-based morphine dose-predicted postoperative RD in our cohort of children undergoing tonsillectomy. More studies with a larger sample size are required to validate this finding.
| S-EPMC8446291 | biostudies-literature
Project description:IntroductionWhole-body plethysmography (WBP) in unrestrained, non-anesthetized rodents is a preclinical method to assess the respiratory depressant effects of opioids, the leading cause of opioid overdose death in humans. However, low baseline respiration rates under normocapnic conditions (i.e., "floor" effect) can render the measurement of respiratory decreases challenging. We assessed hypercapnia-induced increases in respiration as a strategy to assess opioid-induced decreases in respiration in rats.MethodsWBP was used to assess respiration frequency, tidal volume and minute volume in the presence of normocapnic and hypercapnic (8% CO2) conditions in rats during the rat diurnal period of the light cycle. The mu-opioid receptor agonist fentanyl was administered intravenously, and the hot plate test was used to assess acute antinociception.Results and discussionHypercapnia-induced increases in respiratory parameters (frequency, minute volume, and tidal volume) were decreased by fentanyl at doses that did not decrease the same parameters under the normocapnic conditions. These findings show that hypercapnia increases sensitivity to respiratory depressant effects of fentanyl, as compared with assessments during the rat diurnal period when activity and breathing rate are generally low, i.e., there is a floor effect. The current approach is highly sensitive to opioid-induced respiratory depression, and therefore provides a useful method for assessment in a pre-clinical setting.
| S-EPMC8494486 | biostudies-literature
Project description:Background: Opioids are commonly prescribed to hospitalized adults to promote adequate pain relief, yet they can cause potentially fatal respiratory depression. Aim: The aim of this study was to examine the risk factors for the development of severe opioid-induced respiratory depression (OIRD) in hospitalized adults to ensure adequate monitoring of high-risk patients. Methods: A retrospective case-control study was conducted using data from the medical records of a university-affiliated hospital in Canada. Cases were eligible if they were adults (≥18 years old) and received opioid analgesia within 24 h of naloxone administration for respiratory depression. Controls had the same eligibility criteria, except for respiratory depression and naloxone administration. The case-control ratio was 1:1, and they were matched based on sex, type of unit, opioid molecule and the presence/absence of medication errors. Results: A total of 133 cases and 133 controls were included. Following cumulative risk factor analysis, renal failure (odds ratio [OR] = 2.176, 95% confidence interval [CI], 1.021-4.640, P = 0.044), the first 24 h of opioid administration (OR = 1.899, 95% CI, 1.090-3.309, P = 0.024), concomitant central nervous system (CNS) depressants (OR = 1.785, 95% CI, 1.023-3.113, P = 0.041), and increasing age (OR = 1.019, 95% CI, 1.002-1.035, P = 0.028) were positively associated with severe OIRD. Conclusions: Some adult hospitalized patients were at higher risk of experiencing severe OIRD, such as those with renal failure, those in their first 24 h of opioid administration, those receiving CNS depressants in addition to opioids, and those with an advanced age. These results will assist with the screening of patients at higher risk for severe OIRD, which is key to implementing appropriate monitoring and enhancing the safety of opioid use in hospital settings.
| S-EPMC7951145 | biostudies-literature