Opioids depress breathing through two small brainstem sites

eLife, Год журнала: 2020, Номер 9

Опубликована: Фев. 19, 2020

The rates of opioid overdose in the United States quadrupled between 1999 and 2017, reaching a staggering 130 deaths per day. This health epidemic demands innovative solutions that require uncovering key brain areas cell types mediating cause overdose- opioid-induced respiratory depression. Here, we identify two primary changes to murine breathing after administering opioids. These implicate brainstem's circuitry which confirm by locally eliminating µ-Opioid receptor. We find critical site is preBötzinger Complex, where rhythm originates, use genetic tools reveal just 70-140 neurons this region are responsible for its sensitivity Future characterization these may lead novel therapies prevent depression while sparing analgesia.Opioids such as morphine or fentanyl powerful substances used relieve pain medical settings. However, taken too high dose they can depress – other words, slow, shallow breaths cannot sustain life. In States, misuse drugs has been soaring past decades, about people die each day from overdose. Pinpointing exact opioids act on could help create safer painkillers do not have deadly effect. While previous studies proposed several regions be involved, able results, determine area plays biggest role. Opioids influence animals (including humans) attaching proteins known receptors present at surface neurons. Bachmutsky et al. genetically engineered mice lack specific control breathing. were then exposed opioids, their was closely monitored. experiments showed small becoming depressed under with most impact also happens rhythms originate. There, group 50 140 Crucially, cells necessary drugs’ ability pain. Overall, work highlights whose role creating deserves further attention. It opens possibility targeting would painkillers.

Язык: Английский

---

Emergent Elements of Inspiratory Rhythmogenesis: Network Synchronization and Synchrony Propagation

Neuron, Год журнала: 2020, Номер 106(3), С. 482 - 497.e4

Опубликована: Март 3, 2020

Язык: Английский

---

Advancing respiratory–cardiovascular physiology with the working heart–brainstem preparation over 25 years

The Journal of Physiology, Год журнала: 2022, Номер 600(9), С. 2049 - 2075

Опубликована: Март 16, 2022

Abstract Twenty‐five years ago, a new physiological preparation called the working heart–brainstem (WHBP) was introduced with claim it would provide platform allowing studies not possible before in cardiovascular, neuroendocrine, autonomic and respiratory research. Herein, we review some of progress made WHBP, advantages disadvantages along potential future applications, photographs technical drawings all customised equipment used for preparation. Using mice or rats, WHBP is an situ experimental model that perfused via extracorporeal circuit benefitting from unprecedented surgical access, mechanical stability brain whole cell recording uncompromised use pharmacological agents akin to vitro approaches. The has revealed novel mechanistic insights into, example, generation distinct rhythms, neurogenesis sympathetic activity, coupling between respiration heart circulation, hypothalamic spinal control mechanisms, peripheral central chemoreceptor mechanisms. Insights have been gleaned into diseases such as hypertension, failure sleep apnoea. Findings ratified conscious vivo animals when tested translated humans. We conclude by discussing applications including two‐photon imaging nervous systems adoption pharmacogenetic tools will improve our understanding mechanisms reveal may guide treatment strategies cardiorespiratory diseases. image

Язык: Английский

---

Inspiratory and sigh breathing rhythms depend on distinct cellular signalling mechanisms in the preBötzinger complex

The Journal of Physiology, Год журнала: 2024, Номер 602(5), С. 809 - 834

Опубликована: Фев. 14, 2024

Abstract Breathing behaviour involves the generation of normal breaths (eupnoea) on a timescale seconds and sigh order minutes. Both rhythms emerge in tandem from single brainstem site, but whether how cell population can generate two disparate remains unclear. We posit that recurrent synaptic excitation concert with depression cellular refractoriness gives rise to eupnoea rhythm, whereas an intracellular calcium oscillation is slower by orders magnitude rhythm. A mathematical model capturing these dynamics simultaneously generates frequencies, which be separately regulated physiological parameters. experimentally validated key predictions regarding signalling. All vertebrate brains feature network oscillator drives breathing pump for regular respiration. However, air‐breathing mammals compliant lungs susceptible collapse, rhythmogenic may have refashioned ubiquitous signalling systems produce second rhythm (for sighs) prevents atelectasis without impeding eupnoea. image Key points simplified activity‐based preBötC inspiratory neuron population. Inspiration attributable canonical excitatory mechanism. Sigh emerges The predicts perturbations uptake release across endoplasmic reticulum counterintuitively accelerate decelerate rhythmicity, respectively, was validated. Vertebrate evolution adapted existing mechanisms slow oscillations needed optimize pulmonary function mammals.

Язык: Английский

---

Opioids modulate an emergent rhythmogenic process to depress breathing

eLife, Год журнала: 2019, Номер 8

Опубликована: Дек. 16, 2019

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

Язык: Английский

---

Degenerate Neuronal and Circuit Mechanisms Important for Generating Rhythmic Motor Patterns

Physiological Reviews, Год журнала: 2024, Номер 105(1), С. 95 - 135

Опубликована: Июнь 13, 2024

In 1996, we published a review article (Marder E, Calabrese RL.

Язык: Английский

---

Inhibitory control of active expiration by the Bötzinger complex in rats

The Journal of Physiology, Год журнала: 2020, Номер 598(21), С. 4969 - 4994

Опубликована: Июль 4, 2020

Contraction of abdominal muscles at the end expiration during metabolic challenges (such as hypercapnia and hypoxia) improves pulmonary ventilation. The emergence this active expiratory pattern requires recruitment oscillator located on ventral surface medulla oblongata. Here we show that an inhibitory circuitry in Bötzinger complex is important source drive to oscillator. This circuitry, mediated by GABAergic glycinergic synapses, provides inhibition restrains under resting condition regulates formation activity expiration. By combining experimental modelling approaches, propose organization connections within respiratory network control changes breathing associated with elevated demand.The neurons (BötC) provide inputs network, which, eupnoea, are critically for phase transition duration control. Here, investigated how BötC interact parafacial group (pFRG) Using decerebrated, arterially perfused situ preparations juvenile rats, recorded performed pharmacological manipulations pFRG or after exposure short-term sustained hypoxia - conditions generate data were integrated a mathematical model gain new insights into connectome central generator. Our results indicate may establish mutual pFRG, providing first stage receiving excitatory late Moreover, found application antagonists caused opposing effects activity, suggesting BötC. modelling, its interactions restrain contribute observed hypoxia.

Язык: Английский

---

Putting the theory into ‘burstlet theory’ with a biophysical model of burstlets and bursts in the respiratory preBötzinger complex

eLife, Год журнала: 2022, Номер 11

Опубликована: Апрель 5, 2022

Inspiratory breathing rhythms arise from synchronized neuronal activity in a bilaterally distributed brainstem structure known as the preBötzinger complex (preBötC). In vitro slice preparations containing preBötC, extracellular potassium must be elevated above physiological levels (to 7–9 mM) to observe regular rhythmic respiratory motor output hypoglossal nerve which preBötC projects. Reexamination of how K + affects has revealed that low-amplitude oscillations persist at levels. These oscillatory events are subthreshold standpoint transmission and dubbed burstlets. Burstlets neural rhythmogenic subpopulation within some instances may fail recruit larger network events, or bursts, required generate output. The fraction (burstlet fraction) decreases sigmoidally with increasing potassium. observations underlie burstlet theory rhythm generation. Experimental computational studies have suggested recruitment non-rhythmogenic component population requires intracellular Ca 2+ dynamics activation calcium-activated nonselective cationic current. this study, we show calcium driven by synaptically triggered influx well release/uptake endoplasmic reticulum conjunction current can reproduce offer an explanation for many key properties associated Altogether, our modeling work provides mechanistic basis unify wide range experimental findings on generation preBötC.

Язык: Английский

---

Respiratory rhythm and pattern generation: Brainstem cellular and circuit mechanisms

Handbook of clinical neurology, Год журнала: 2022, Номер unknown, С. 1 - 35

Опубликована: Янв. 1, 2022

Язык: Английский

---

Interdependence of cellular and network properties in respiratory rhythm generation

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(19)

Опубликована: Май 1, 2024

How breathing is generated by the preBötzinger complex (preBötC) remains divided between two ideological frameworks, and a persistent sodium current (I

Язык: Английский

---