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1.
Respir Physiol Neurobiol ; 331: 104354, 2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39389523

RESUMO

INTRODUCTION: The genioglossus (GG) is known to be the main tongue protrusor, and therefore plays a major role in breathing. However, due to the fan shape of the GG fibers, it could be assumed that contraction of the anterior fibers of the GG do not cause tongue protrusion. In this study, we examined the effect of contraction of the anterior-vertical fibers of the GG (GGV) on the tongue and their EMG activity during wakefulness and sleep. The findings were compared to those of the longitudinal fibers (GGL), which, based on their orientation, are responsible for tongue protrusion. METHODS: Fine-wire electrode pairs were placed into the GGV and GGL in 11 patients with untreated OSA. Movement of the tongue during electrical stimulation at each site was videoed. The same electrodes were used to record EMG from both sites during respiratory stimulation by inspiratory loading and CO2 rebreathing during wakefulness. During sleep, repetitive flow limitation events were induced with low-level CPAP to augment GG activity. RESULTS: In all participants, electrical stimulation of GGL and GGV protruded and retracted the tongue, respectively. Respiratory stimulation increased GG activity, but GGV reached only 39 % and 23 % of peak GGL activity during high resistive loading and PCO2 of 65 mmHg, respectively. Flow limitation during sleep increased GGL to levels that were considerably higher than awake baseline, but GGV activity remained tonic or with minimal phasic activity, reaching on average 15 % of GGL peak activity. CONCLUSIONS: Our electrical stimulation findings indicate that GGV is a tongue retractor and depressor. Tongue stimulation for OSA should avoid this area. The EMG results demonstrate that the anterior part of the GG is controlled very differently from the longitudinal protrusive fibers. The GGV responses are similar to those previously found in tongue retractors and peri-pharyngeal muscles other than the GG, in which diminished activation during sleep is likely to be involved in the failure of increasing GGL activity to alleviate flow limitation.

2.
Sleep Med Clin ; 19(4): 625-638, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39455182

RESUMO

Opioid use disorder (OUD) is a chronic and relapsing brain disease characterized by loss of control over opioid use and impairments in cognitive function, mood, pain perception, and autonomic activity. Sleep deficiency, a term that encompasses insufficient or disrupted sleep due to multiple potential causes, including sleep disorders (eg, insomnia, sleep apnea), circadian disruption (eg, delayed sleep phase and social jet lag), and poor sleep quality (eg, sleep fragmentation, impaired sleep architecture), is present in greater than 75% of patients with OUD. This article focuses on highlighting bidirectional mechanisms between OUD and sleep deficiency and points toward promising therapeutic targets.


Assuntos
Transtornos Relacionados ao Uso de Opioides , Transtornos do Sono-Vigília , Humanos , Transtornos Relacionados ao Uso de Opioides/terapia , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Transtornos do Sono-Vigília/terapia , Transtornos do Sono-Vigília/fisiopatologia
3.
Am J Physiol Regul Integr Comp Physiol ; 327(4): R400-R409, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39102461

RESUMO

Hyperthermia stimulates ventilation in humans. This hyperthermia-induced hyperventilation may be mediated by the activation of peripheral chemoreceptors implicated in the regulation of respiration in reaction to various chemical stimuli, including reductions in arterial pH. Here, we investigated the hypothesis that during passive heating at rest, the increases in arterial pH achieved with sodium bicarbonate ingestion, which could attenuate peripheral chemoreceptor activity, mitigate hyperthermia-induced hyperventilation. We also assessed the effect of sodium bicarbonate ingestion on cerebral blood flow responses, which are associated with hyperthermia-induced hyperventilation. Twelve healthy men ingested sodium bicarbonate (0.3 g/kg body weight) or sodium chloride (0.208 g/kg). One hundred minutes after the ingestion, the participants were passively heated using hot-water immersion (42°C) combined with a water-perfused suit. Increases in esophageal temperature (an index of core temperature) and minute ventilation (V̇E) during the heating were similar in the two trials. Moreover, when V̇E is expressed as a function of esophageal temperature, there were no between-trial differences in the core temperature threshold for hyperventilation (38.0 ± 0.3 vs. 38.0 ± 0.4°C, P = 0.469) and sensitivity of hyperthermia-induced hyperventilation as assessed by the slope of the core temperature-V̇E relation (13.5 ± 14.2 vs. 15.8 ± 15.5 L/min/°C, P = 0.831). Furthermore, middle cerebral artery mean blood velocity (an index of cerebral blood flow) decreased similarly with heating duration in both trials. These results suggest that sodium bicarbonate ingestion does not mitigate hyperthermia-induced hyperventilation and the reductions in cerebral blood flow index in resting heated humans.NEW & NOTEWORTHY Hyperthermia leads to hyperventilation and associated cerebral hypoperfusion, both of which may impair heat tolerance. This hyperthermia-induced hyperventilation may be mediated by peripheral chemoreceptors, which can be activated by reductions in arterial pH. However, our results suggest that sodium bicarbonate ingestion, which can increase arterial pH, is not an effective intervention in alleviating hyperthermia-induced hyperventilation and cerebral hypoperfusion in resting heated humans.


Assuntos
Circulação Cerebrovascular , Hiperventilação , Bicarbonato de Sódio , Humanos , Masculino , Bicarbonato de Sódio/farmacologia , Bicarbonato de Sódio/administração & dosagem , Circulação Cerebrovascular/efeitos dos fármacos , Adulto , Hiperventilação/fisiopatologia , Adulto Jovem , Concentração de Íons de Hidrogênio , Ventilação Pulmonar/efeitos dos fármacos , Células Quimiorreceptoras/efeitos dos fármacos , Células Quimiorreceptoras/metabolismo , Hipertermia/fisiopatologia , Temperatura Alta , Descanso/fisiologia , Regulação da Temperatura Corporal/efeitos dos fármacos
4.
Sleep Med Clin ; 19(3): 379-389, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39095137

RESUMO

Chronic hypercapnic respiratory failure occurs in several conditions associated with hypoventilation. The mechanisms underlying the development of chronic hypercapnia include a combination of processes that increase metabolic CO2 production, reduce minute ventilation (V'e), or increase dead space fraction (Vd/Vt). Fundamental to the pathophysiology is a mismatch between increased load and a reduction in the capacity of the respiratory pump to compensate. Though neural respiratory drive may be decreased in a subset of central hypoventilation disorders, it is more commonly increased in attempting to maintain the load-capacity homeostatic balance.


Assuntos
Hipercapnia , Insuficiência Respiratória , Humanos , Hipercapnia/fisiopatologia , Insuficiência Respiratória/fisiopatologia , Insuficiência Respiratória/terapia , Doença Crônica , Hipoventilação/fisiopatologia , Hipoventilação/terapia
5.
Respir Physiol Neurobiol ; 329: 104317, 2024 11.
Artigo em Inglês | MEDLINE | ID: mdl-39187051

RESUMO

Chronic hypoxia (CH) during postnatal development attenuates the hypoxic ventilatory response (HVR) in mammals, but there are conflicting reports on whether this plasticity is permanent or reversible. This study tested the hypothesis that CH-induced respiratory plasticity is reversible in neonatal rats and investigated whether the initial plasticity or recovery differs between sexes. Rat pups were exposed to 3 d of normobaric CH (12 % O2) beginning shortly after birth. Ventilation and metabolic CO2 production were then measured in normoxia and during an acute hypoxic challenge (12 % O2) immediately following CH and after 1, 4-5, and 7 d in room air. CH pups hyperventilated when returned to normoxia immediately following CH, but normoxic ventilation was similar to age-matched control rats within 7 d after return to room air. The early phase of the HVR (minute 1) was only blunted immediately following the CH exposure, while the late phase of the HVR (minute 15) remained blunted after 1 and 4-5 d in room air; recovery appeared complete by 7 d. However, when normalized to CO2 production, the late phase of the hypoxic response recovered within only 1 d. The initial blunting of the HVR and subsequent recovery were similar in female and male rats. Carotid body responses to hypoxia (in vitro) were also normal in CH pups after approximately one week in room air. Collectively, these data indicate that ventilatory and metabolic responses to hypoxia recover rapidly in both female and male neonatal rats once normoxia is restored following CH.


Assuntos
Animais Recém-Nascidos , Dióxido de Carbono , Hipóxia , Ratos Sprague-Dawley , Animais , Hipóxia/metabolismo , Hipóxia/fisiopatologia , Masculino , Feminino , Ratos , Dióxido de Carbono/metabolismo , Ventilação Pulmonar/fisiologia , Recuperação de Função Fisiológica/fisiologia , Doença Crônica , Modelos Animais de Doenças
6.
Exp Physiol ; 109(9): 1426-1445, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39023735

RESUMO

Duchenne muscular dystrophy (DMD) is a fatal genetic neuromuscular disease. Lack of dystrophin in skeletal muscles leads to intrinsic weakness, injury, subsequent degeneration and fibrosis, decreasing contractile function. Dystropathology eventually presents in all inspiratory and expiratory muscles of breathing, severely curtailing their critical function. In people with DMD, premature death is caused by respiratory or cardiac failure. There is an urgent need to develop therapies that improve quality of life and extend life expectancy in DMD. Surprisingly, there is a dearth of information on respiratory control in animal models of DMD, and respiratory outcome measures are often limited or absent in clinical trials. Characterization of respiratory performance in murine and canine models has revealed extensive remodelling of the diaphragm, the major muscle of inspiration. However, significant compensation by extradiaphragmatic muscles of breathing is evident in early disease, contributing to preservation of peak respiratory system performance. Loss of compensation afforded by accessory muscles in advanced disease is ultimately associated with compromised respiratory performance. A new and potentially more translatable murine model of DMD, the D2.mdx mouse, has recently been developed. Respiratory performance in D2.mdx mice is yet to be characterized fully. However, based on histopathological features, D2.mdx mice might serve as useful preclinical models, facilitating the testing of new therapeutics that rescue respiratory function. This review summarizes the pathophysiological mechanisms associated with DMD both in humans and in animal models, with a focus on breathing. We consider the translational value of each model to human DMD and highlight the urgent need for comprehensive characterization of breathing in representative preclinical models to better inform human trials.


Assuntos
Modelos Animais de Doenças , Distrofia Muscular de Duchenne , Distrofia Muscular de Duchenne/fisiopatologia , Animais , Humanos , Camundongos , Camundongos Endogâmicos mdx , Cães , Diafragma/fisiopatologia , Músculos Respiratórios/fisiopatologia , Respiração , Músculo Esquelético/fisiopatologia , Músculo Esquelético/metabolismo
7.
J Neurophysiol ; 131(6): 1188-1199, 2024 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-38691529

RESUMO

Prolonged inhibition of respiratory neural activity elicits a long-lasting increase in phrenic nerve amplitude once respiratory neural activity is restored. Such long-lasting facilitation represents a form of respiratory motor plasticity known as inactivity-induced phrenic motor facilitation (iPMF). Although facilitation also occurs in inspiratory intercostal nerve activity after diminished respiratory neural activity (iIMF), it is of shorter duration. Atypical PKC activity in the cervical spinal cord is necessary for iPMF and iIMF, but the site and specific isoform of the relevant atypical PKC are unknown. Here, we used RNA interference to test the hypothesis that the zeta atypical PKC isoform (PKCζ) within phrenic motor neurons is necessary for iPMF but PKCζ within intercostal motor neurons is unnecessary for transient iIMF. Intrapleural injections of siRNAs targeting PKCζ (siPKCζ) to knock down PKCζ mRNA within phrenic and intercostal motor neurons were made in rats. Control rats received a nontargeting siRNA (NTsi) or an active siRNA pool targeting a novel PKC isoform, PKCθ (siPKCθ), which is required for other forms of respiratory motor plasticity. Phrenic nerve burst amplitude and external intercostal (T2) electromyographic (EMG) activity were measured in anesthetized and mechanically ventilated rats exposed to 30 min of respiratory neural inactivity (i.e., neural apnea) created by modest hypocapnia (20 min) or a similar recording duration without neural apnea (time control). Phrenic burst amplitude was increased in rats treated with NTsi (68 ± 10% baseline) and siPKCθ (57 ± 8% baseline) 60 min after neural apnea vs. time control rats (-3 ± 3% baseline), demonstrating iPMF. In contrast, intrapleural siPKCζ virtually abolished iPMF (5 ± 4% baseline). iIMF was transient in all groups exposed to neural apnea; however, intrapleural siPKCζ attenuated iIMF 5 min after neural apnea (50 ± 21% baseline) vs. NTsi (97 ± 22% baseline) and siPKCθ (103 ± 20% baseline). Neural inactivity elevated the phrenic, but not intercostal, responses to hypercapnia, an effect that was blocked by siPKCζ. We conclude that PKCζ within phrenic motor neurons is necessary for long-lasting iPMF, whereas intercostal motor neuron PKCζ contributes to, but is not necessary for, transient iIMF.NEW & NOTEWORTHY We report important new findings concerning the mechanisms regulating a form of spinal neuroplasticity elicited by prolonged inhibition of respiratory neural activity, inactivity-induced phrenic motor facilitation (iPMF). We demonstrate that the atypical PKC isoform PKCζ within phrenic motor neurons is necessary for long-lasting iPMF, whereas intercostal motor neuron PKCζ contributes to, but is not necessary for, transient inspiratory intercostal facilitation. Our findings are novel and advance our understanding of mechanisms contributing to phrenic motor plasticity.


Assuntos
Neurônios Motores , Nervo Frênico , Proteína Quinase C , Ratos Sprague-Dawley , Animais , Nervo Frênico/fisiologia , Proteína Quinase C/metabolismo , Proteína Quinase C/fisiologia , Neurônios Motores/fisiologia , Masculino , Ratos , Plasticidade Neuronal/fisiologia
8.
Front Physiol ; 15: 1334874, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38784113

RESUMO

Background: High-altitude populations exhibit distinct cellular, respiratory, and cardiovascular phenotypes, some of which provide adaptive advantages to hypoxic conditions compared to populations with sea-level ancestry. Studies performed in populations with a history of high-altitude residence, such as Tibetans, support the idea that many of these phenotypes may be shaped by genomic features that have been positively selected for throughout generations. We hypothesize that such traits observed in Tibetans at high altitude also occur in Tibetans living at intermediate altitude, even in the absence of severe sustained hypoxia. Methodology: We studied individuals of high-altitude ancestry (Tibetans, n = 17 females; n = 12 males) and sea-level ancestry (Han Chinese, n = 6 females; n = 10 males), both who had been living at ∼1300 m (∼4327 ft) for at least 18 months. We measured hemoglobin concentration ([Hb]), hypoxic ventilatory response (HVR), and hypoxic heart rate response (HHRR) with end-tidal CO2 (PetCO2) held constant (isocapnia) or allowed to decrease with hypoxic hyperventilation (poikilocapnia). We also quantified the contribution of CO2 on ventilation and heart rate by calculating the differences of isocapnic versus poikilocapnic hypoxic conditions (Δ V˙I/ΔPetCO2 and ΔHR/ΔPetCO2, respectively). Results: Male Tibetans had lower [Hb] compared to Han Chinese males (p < 0.05), consistent with reports for individuals from these populations living at high altitude and sea level. Measurements of ventilation (resting ventilation, HVR, and PetCO2) were similar for both groups. Heart rate responses to hypoxia were similar in both groups during isocapnia; however, HHRR in poikilocapnia was reduced in the Tibetan group (p < 0.03), and the heart rate response to CO2 in hypoxia was lower in Tibetans relative to Han Chinese (p < 0.01). Conclusion: These results suggest that Tibetans living at intermediate altitude have blunted cardiac responses in the context of hypoxia. Hence, only some of the phenotypes observed in Tibetans living at high altitude are observed in Tibetans living at intermediate altitude. Whereas blunted cardiac responses to hypoxia is revealed at intermediate altitudes, manifestation of other physiological adaptations to high altitude may require exposure to more severe levels of hypoxia.

9.
EClinicalMedicine ; 68: 102417, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38235422

RESUMO

Background: Sedation management has a major impact on outcomes in mechanically ventilated patients, but sedation strategies do not generally consider the differential effects of different sedatives on respiration and respiratory pattern. A systematic review was undertaken to quantitatively summarize the known effects of different classes of drugs used for sedation on respiratory pattern during both spontaneous breathing and assisted mechanical ventilation. Methods: This was a systematic review and meta-analysis conducted using Ovid MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials up to June 2020 to retrieve studies that measured respiratory parameters before and after the administration of opioids, benzodiazepines, intravenous and inhaled anaesthetic agents, and other hypnotic agents (PROSPERO #CRD42020190017). A random-effects meta-analytic model was employed to estimate the mean percentage change in each of the respiratory indices according to medication exposure with and without mechanical ventilation. Risk of bias was assessed using the Cochrane risk of bias assessment tools. Findings: Fifty-one studies were included in the analysis. Risk of bias was generally deemed to be low for most studies. Respiratory rate decreased with the administration of opioids in both non-ventilated patients (18% decrease, 95% CI 12-24%) and ventilated patients (26% decrease, 95% CI 15-37%) and increased with inhaled anaesthetics in non-ventilated patients (83% increase, 95% CI 49-118%) and ventilated patients (50% increase, 28-72%). In non-ventilated patients, tidal volume decreased following administration of inhaled aesthetics (55% decrease, 95% CI 25-86%), propofol (36% decrease, 95% CI 20-52%), and benzodiazepines (28% decrease, 95% CI 17-40%); in patients receiving assisted mechanical ventilation, tidal volume was not significantly affected by sedation. Administration of other hypnotic agents was not associated with changes in respiratory rate or tidal volume. Interpretation: Different classes of drugs used for sedation exert differential effects on respiratory pattern, and this may influence weaning and outcomes in mechanically ventilated patients. Funding: This study did not receive any funding support.

10.
Adv Physiol Educ ; 48(2): 238-251, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38205515

RESUMO

The pulmonary system is the first and last "line of defense" in terms of maintaining blood gas homeostasis during exercise. Our review provides the reader with an overview of how the pulmonary system responds to acute exercise. We undertook this endeavor to provide a companion article to "Cardiovascular Response to Exercise," which was published in Advances in Physiological Education. Together, these articles provide the readers with a solid foundation of the cardiopulmonary response to acute exercise in healthy individuals. The intended audience of this review is level undergraduate or graduate students and/or instructors for such classes. By intention, we intend this to be used as an educational resource and seek to provide illustrative examples to reinforce topics as well as highlight uncertainty to encourage the reader to think "beyond the textbook." Our treatment of the topic presents "classic" concepts along with new information on the pulmonary physiology of healthy aging.NEW & NOTEWORTHY Our narrative review is written with the student of the pulmonary physiology of exercise in mind, be it a senior undergraduate or graduate student or those simply refreshing their knowledge. We also aim to provide examples where the reader can incorporate real scenarios.


Assuntos
Fisiologia , Fenômenos Fisiológicos Respiratórios , Humanos , Pulmão/fisiologia , Exercício Físico/fisiologia , Estudantes , Troca Gasosa Pulmonar , Teste de Esforço , Fisiologia/educação
11.
Respir Physiol Neurobiol ; 320: 104188, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37939866

RESUMO

Breathing requires distinct patterns of neuronal activity in the brainstem. The most critical part of the neuronal network responsible for respiratory rhythm generation is the preBötzinger Complex (preBötC), located in the ventrolateral medulla. This area contains both rhythmogenic glutamatergic neurons and also a high number of inhibitory neurons. Here, we aimed to analyze the activity of glycinergic neurons in the preBötC in anesthetized mice. To identify inhibitory neurons, we used a transgenic mouse line that allows expression of Channelrhodopsin 2 in glycinergic neurons. Using juxtacellular recordings and optogenetic activation via a single recording electrode, we were able to identify neurons as inhibitory and define their activity pattern in relation to the breathing rhythm. We could show that the activity pattern of glycinergic respiratory neurons in the preBötC was heterogeneous. Interestingly, only a minority of the identified glycinergic neurons showed a clear phase-locked activity pattern in every respiratory cycle. Taken together, we could show that neuron identification is possible by a combination of juxtacellular recordings and optogenetic activation via a single recording electrode.


Assuntos
Optogenética , Centro Respiratório , Camundongos , Animais , Centro Respiratório/fisiologia , Neurônios/metabolismo , Bulbo/fisiologia , Camundongos Transgênicos
12.
J Physiol ; 602(1): 93-112, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38063489

RESUMO

The Kölliker-Fuse nucleus (KF), which is part of the parabrachial complex, participates in the generation of eupnoea under resting conditions and the control of active abdominal expiration when increased ventilation is required. Moreover, dysfunctions in KF neuronal activity are believed to play a role in the emergence of respiratory abnormalities seen in Rett syndrome (RTT), a progressive neurodevelopmental disorder associated with an irregular breathing pattern and frequent apnoeas. Relatively little is known, however, about the intrinsic dynamics of neurons within the KF and how their synaptic connections affect breathing pattern control and contribute to breathing irregularities. In this study, we use a reduced computational model to consider several dynamical regimes of KF activity paired with different input sources to determine which combinations are compatible with known experimental observations. We further build on these findings to identify possible interactions between the KF and other components of the respiratory neural circuitry. Specifically, we present two models that both simulate eupnoeic as well as RTT-like breathing phenotypes. Using nullcline analysis, we identify the types of inhibitory inputs to the KF leading to RTT-like respiratory patterns and suggest possible KF local circuit organizations. When the identified properties are present, the two models also exhibit quantal acceleration of late-expiratory activity, a hallmark of active expiration featuring forced exhalation, with increasing inhibition to KF, as reported experimentally. Hence, these models instantiate plausible hypotheses about possible KF dynamics and forms of local network interactions, thus providing a general framework as well as specific predictions for future experimental testing. KEY POINTS: The Kölliker-Fuse nucleus (KF), a part of the parabrachial complex, is involved in regulating normal breathing and controlling active abdominal expiration during increased ventilation. Dysfunction in KF neuronal activity is thought to contribute to respiratory abnormalities seen in Rett syndrome (RTT). This study utilizes computational modelling to explore different dynamical regimes of KF activity and their compatibility with experimental observations. By analysing different model configurations, the study identifies inhibitory inputs to the KF that lead to RTT-like respiratory patterns and proposes potential KF local circuit organizations. Two models are presented that simulate both normal breathing and RTT-like breathing patterns. These models provide testable hypotheses and specific predictions for future experimental investigations, offering a general framework for understanding KF dynamics and potential network interactions.


Assuntos
Núcleo de Kölliker-Fuse , Síndrome de Rett , Humanos , Núcleo de Kölliker-Fuse/fisiologia , Respiração , Neurônios , Simulação por Computador
13.
J Exp Biol ; 226(24)2023 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-38009047

RESUMO

It is well established that arterial pH decreases with increased temperature in amphibians and reptiles through an elevation of arterial PCO2, but the underlying regulation remains controversial. The alphastat hypothesis ascribes the pH fall to a ventilatory regulation of protein ionisation, but the pH reduction with temperature is lower than predicted by the pKa change of the imidazole group on histidine. We hypothesised that arterial pH decreases at high, but not at low, temperatures when toads (Rhinella marina) and snakes (Python molurus) are exposed to hyperoxia. In toads, hyperoxia caused similar elevations of arterial PCO2 at 20 and 30°C, indicative of a temperature-independent oxygen-mediated drive to breathing, whereas PCO2 was unaffected by hyperoxia in snakes at 25 and 35°C. These findings do not support our hypothesis of an increased oxygen-mediated drive to breathing as body temperature increases.


Assuntos
Boidae , Hiperóxia , Animais , Temperatura , Bufo marinus , Oxigênio/metabolismo , Concentração de Íons de Hidrogênio
14.
J Physiol ; 601(20): 4625-4642, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37778015

RESUMO

This study provides an in-depth analysis of the distinct consequences of the opioid drugs morphine and fentanyl during opioid-induced respiratory depression (OIRD). We explored the physiological implications of both drugs on ventilation and airway patency in anaesthetized mice. Our results revealed a similar reduction in respiratory frequency with equivalent scaled dosages of fentanyl and morphine, though the onset of suppression was more rapid with fentanyl. Additionally, fentanyl resulted in transient airflow obstructions during the inspiratory cycle, which were absent following morphine administration. Notably, these fentanyl-specific obstructions were eliminated with tracheostomy, implicating the upper airways as a major factor contributing to fentanyl-induced respiratory depression. We further demonstrate that bronchodilators salbutamol and adrenaline effectively reversed these obstructions, highlighting the bronchi's contribution to fentanyl-induced airflow obstruction. Our study also uncovered a significant reduction in sighs during OIRD, which were eliminated by fentanyl and markedly reduced by morphine. Finally, we found that fentanyl-exposed mice had reduced survival under hypoxic conditions compared to mice given morphine, demonstrating that fentanyl becomes more lethal in the context of hypoxaemia. Our findings shed light on the distinct and profound impacts of these opioids on respiration and airway stability and lay the foundation for improved opioid use guidelines and more effective OIRD prevention strategies. KEY POINTS: Both morphine and fentanyl significantly suppressed respiratory frequency, but the onset of suppression was faster with fentanyl. Also, while both drugs increased tidal volume, this effect was more pronounced with fentanyl. Fentanyl administration resulted in transient obstructions during the inspiratory phase, suggesting its unique impact on airway stability. This obstruction was not observed with morphine. The fentanyl-induced obstructions were reversed by administering bronchodilators such as salbutamol and adrenaline. This suggests a possible therapeutic strategy for mitigating the adverse airway effects of fentanyl. Both drugs reduced the frequency of physiological sighs, a key mechanism to prevent alveolar collapse. However, fentanyl administration led to a complete cessation of sighs, while morphine only reduced their occurrence. Fentanyl-treated mice showed a significantly reduced ability to survive under hypoxic conditions compared to those administered morphine. This indicates that the impacts of hypoxaemia during opioid-induced respiratory depression can vary based on the opioid used.


Assuntos
Morfina , Insuficiência Respiratória , Camundongos , Animais , Morfina/farmacologia , Fentanila/farmacologia , Analgésicos Opioides , Broncodilatadores/efeitos adversos , Respiração , Insuficiência Respiratória/induzido quimicamente , Hipóxia , Albuterol , Epinefrina
15.
bioRxiv ; 2023 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-37873475

RESUMO

The respiratory network must produce consistent output throughout an animal's life. Although respiratory motor plasticity is well appreciated, how plasticity mechanisms are organized to give rise to robustness following perturbations that disrupt breathing is less clear. During underwater hibernation, respiratory neurons of bullfrogs remain inactive for months, providing a large disturbance that must be overcome to restart breathing. As a result, motoneurons upregulate excitatory synapses to promote the drive to breathe. Reduced inhibition often occurs in parallel with increased excitation, yet the loss of inhibition can destabilize respiratory motor output. Thus, we hypothesized that GABAergic inhibition would decrease following hibernation, but this decrease would be expressed differentially throughout the network. We confirmed that respiratory frequency was under control of GABAAR signaling, but after hibernation, it became less reliant on inhibition. The loss of inhibition was confined to the respiratory rhythm-generating centers: non-respiratory motor activity and large seizure-like bursts were similarly triggered by GABAA receptor blockade in controls and hibernators. Supporting reduced presynaptic GABA release, firing rate of respiratory motoneurons was constrained by a phasic GABAAR tone, but after hibernation, this tone was decreased despite the same postsynaptic receptor strength as controls. Thus, selectively reducing inhibition in respiratory premotor networks promotes stability of breathing, while wholesale loss of GABAARs causes non-specific hyperexcitability throughout the brainstem. These results suggest that different parts of the respiratory network select distinct strategies involving either excitation (motoneurons) or inhibition (rhythm generator) to minimize pathological network states when engaging plasticity that protects the drive to breathe.

16.
Front Physiol ; 14: 1277601, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37885800

RESUMO

Synthetic opioids like fentanyl have improved the standard of care for many patients in the clinical setting, but their abuse leads to tens of thousands of overdose deaths annually. The current opioid epidemic underscores a critical need for insights into the physiological effects of fentanyl on vital functions. High doses of opioids in small mammals cause opioid-induced respiratory depression (OIRD) leading to hypoventilation, hypoxemia, and hypercapnia. In addition, opioids can also increase the alveolar to arterial oxygen (A-a) gradient and airway dysfunction. However, little is known about the physiologic effects of sub-lethal doses of opioids in large mammals. Here we report the effects of a sub-lethal dose range of fentanyl (25-125 µg/kg; IV) on vital physiologic functions over 90 min (min) and withdrawal-like behaviors over the subsequent 4 h (h) in adult female goats (n = 13). Fentanyl induced decreases in breathing frequency in the first few min post-injection, but then led to a sustained increase in tidal volume, total ventilation, and blood pressure with a reduced heart rate for ≥90 min. These ventilatory changes resulted in time-dependent arterial hypocapnia and hypoxemia and an increased alveolar to arterial oxygen gradient ∼30 min post-injection indicative of impaired gas exchange in the lung. The predominant effects of fentanyl on breathing were stimulatory, underscored by an increased rate of rise of the diaphragm muscle activity and increased activation of upper airway, intercostal and abdominal muscles. Beginning 90 min post-injection we also quantified withdrawal-like behaviors over 4 h, demonstrating dose- and time-dependent increases in locomotor, biting, itching, and pawing behaviors. We conclude that fentanyl at sublethal doses induces multiple physiologic and behavior changes that emerge along different time courses suggesting multiple independent mechanisms underlying effects of opioids.

17.
Front Physiol ; 14: 1237376, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37693007

RESUMO

The neuronal activity in the respiratory network strongly depends on a variety of different neuromodulators. Given the essential role of astrocytes in stabilizing respiratory network activity generated by neurons in the preBötzinger complex (preBötC), our aim was to investigate astrocytic calcium signaling in the working heart brainstem preparation using fiber-optical imaging. By using transgenic mice that express GCaMP6s specifically in astrocytes, we successfully recorded astrocytic calcium signals in response to norepinephrine from individual astrocytes.

18.
J Exp Biol ; 226(18)2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37665261

RESUMO

Breathing is generated by a rhythmic neural circuit in the brainstem, which contains conserved elements across vertebrate groups. In adult frogs, the 'lung area' located in the reticularis parvocellularis is thought to represent the core rhythm generator for breathing. Although this region is necessary for breathing-related motor output, whether it functions as an endogenous oscillator when isolated from other brainstem centers is not clear. Therefore, we generated thick brainstem sections that encompass the lung area to determine whether it can generate breathing-related motor output in a highly reduced preparation. Brainstem sections did not produce activity. However, subsaturating block of glycine receptors reliably led to the emergence of rhythmic motor output that was further enhanced by blockade of GABAA receptors. Output occurred in singlets and multi-burst episodes resembling the intact network. However, burst frequency was slower and individual bursts had longer durations than those produced by the intact preparation. In addition, burst frequency was reduced by noradrenaline and µ-opioids, and increased by serotonin, as observed in the intact network and in vivo. These results suggest that the lung area can be activated to produce rhythmic respiratory-related motor output in a reduced brainstem section and provide new insights into respiratory rhythm generation in adult amphibians. First, clustering breaths into episodes can occur within the rhythm-generating network without long-range input from structures such as the pons. Second, local inhibition near, or within, the rhythmogenic center may need to be overridden to express the respiratory rhythm.


Assuntos
Tronco Encefálico , Norepinefrina , Animais , Rana catesbeiana , Respiração , Anuros
19.
J Physiol ; 601(20): 4591-4609, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37566804

RESUMO

How central and peripheral chemoreceptor drives to breathe interact in humans remains contentious. We measured the peripheral chemoreflex sensitivity to hypoxia (PChS) at various isocapnic CO2 tensions ( P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) to determine the form of the relationship between PChS and central P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ . Twenty participants (10F) completed three repetitions of modified rebreathing tests with end-tidal P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ ( P ET O 2 ${P_{{\mathrm{ET}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) clamped at 150, 70, 60 and 45 mmHg. End-tidal P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ( P ETC O 2 ${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ), P ET O 2 ${P_{{\mathrm{ET}}{{\mathrm{O}}_{\mathrm{2}}}}}$ , ventilation ( V ̇ $\dot{V}$ E ) and calculated oxygen saturation (SC O2 ) were measured breath-by-breath by gas-analyser and pneumotach. The V ̇ $\dot{V}$ E - P ETC O 2 ${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ relationship of repeat-trials were linear-interpolated, combined, averaged into 1 mmHg bins, and fitted with a double-linear function ( V ̇ $\dot{V}$ E S, L min-1 mmHg-1 ). PChS was computed at intervals of 1 mmHg of P ETC O 2 ${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ as follows: the difference in V ̇ $\dot{V}$ E between the three hypoxic profiles and the hyperoxic profile (∆ V ̇ $\dot{V}$ E ) was calculated; three ∆ V ̇ $\dot{V}$ E values were plotted against corresponding SC O2 ; and linear regression determined PChS (Lmin-1 mmHg-1 %SC O2 -1 ). These processing steps were repeated at each P ETC O 2 ${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ to produce the PChS vs. isocapnic P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ relationship. These were fitted with linear and polynomial functions, and Akaike information criterion identified the best-fit model. One-way repeated measures analysis of variance assessed between-condition differences. V ̇ $\dot{V}$ E S increased (P < 0.0001) with isoxic P ET O 2 ${P_{{\mathrm{ET}}{{\mathrm{O}}_{\mathrm{2}}}}}$ from 3.7 ± 1.5 L min-1 mmHg-1 at 150 mmHg to 4.4 ± 1.8, 5.0 ± 1.6 and 6.0 ± 2.2 Lmin-1 mmHg-1 at 70, 60 and 45 mmHg, respectively. Mean SC O2 fell progressively (99.3 ± 0%, 93.7 ± 0.1%, 90.4 ± 0.1% and 80.5 ± 0.1%; P < 0.0001). In all individuals, PChS increased with P ETC O 2 ${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ , and this relationship was best described by a linear model in 75%. Despite increasing central chemoreflex activation, PChS increased linearly with P ETC O 2 ${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ indicative of an additive central-peripheral chemoreflex response. KEY POINTS: How central and peripheral chemoreceptor drives to breathe interact in humans remains contentious. We measured peripheral chemoreflex sensitivity to hypoxia (PChS) at various isocapnic carbon dioxide tensions ( P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) to determine the form of the relationship between PChS and central P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ . Participants performed three repetitions of modified rebreathing with end-tidal P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ fixed at 150, 70, 60 and 45 mmHg. PChS was computed at intervals of 1 mmHg of end-tidal P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ( P ETC O 2 ${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ ) as follows: the difference in V ̇ $\dot{V}$ E between the three hypoxic profiles and the hyperoxic profile (∆ V ̇ $\dot{V}$ E ) was calculated; three ∆ V ̇ $\dot{V}$ E values were plotted against corresponding calculated oxygen saturation (SC O2 ); and linear regression determined PChS (Lmin-1 mmHg-1 %SC O2 -1 ). In all individuals, PChS increased with P ETC O 2 ${P_{{\mathrm{ETC}}{{\mathrm{O}}_{\mathrm{2}}}}}$ , and this relationship was best described by a linear (rather than polynomial) model in 15 of 20. Most participants did not exhibit a hypo- or hyper-additive effect of central chemoreceptors on the peripheral chemoreflex indicating that the interaction was additive.

20.
J Exp Biol ; 226(17)2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37534524

RESUMO

Migratory flight requires birds to maintain intensive aerobic exercise for many hours or days. Maintaining O2 supply to flight muscles is therefore important during migration, especially since migratory songbirds have been documented flying at altitudes greater than 5000 m above sea level, where O2 is limited. Whether songbirds exhibit seasonal plasticity of the O2 cascade to maintain O2 uptake and transport during migratory flight is not well understood. We investigated changes in the hypoxic ventilatory response, haematology and pectoralis (flight) muscle phenotype of 6 songbird species from 3 families during migratory and non-migratory conditions. Songbirds were captured during southbound migration in southern Ontario, Canada. Half of the birds were assessed during migration, and the rest were transitioned onto a winter photoperiod to induce a non-migratory phenotype and measured. All species exhibited seasonal plasticity at various stages along the O2 cascade, but not all species exhibited the same responses. Songbirds tended to be more hypoxia tolerant during migration, withstanding 5 kPa O2 and breathed more effectively through slower, deeper breaths. Warblers had a stronger haemoglobin-O2 affinity during autumn migration (decrease of ∼4.7 Torr), while the opposite was observed in thrushes (increase of ∼2.6 Torr). In the flight muscle there was an ∼1.2-fold increase in the abundance of muscle fibres with smaller fibre transverse areas during autumn migration, but no changes in capillary:fibre ratio. These adjustments would enhance O2 uptake and transport to the flight muscle. Our findings demonstrate that in the O2 cascade there is no ideal migratory phenotype for all songbirds.


Assuntos
Aves Canoras , Animais , Aves Canoras/fisiologia , Estações do Ano , Oxigênio , Migração Animal/fisiologia , Músculos Peitorais
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