Functional Modulation of Retrotrapezoid Neurons Drives Fentanyl-Induced Respiratory Depression

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Abstract The primary cause of death from opioid overdose is opioid-induced respiratory depression (OIRD), characterized by severe suppression rate, destabilized breathing patterns, hypercapnia, and heightened risk apnea. retrotrapezoid nucleus (RTN), a critical chemosensitive brainstem region in the rostral ventrolateral medullary reticular formation contains Phox2b + /Neuromedin-B ( Nmb ) propriobulbar neurons. These neurons, stimulated CO 2 /H , regulate to prevent acidosis. Since RTN shows limited expression opioid-receptors, we expected that hypoventilation should activate these neurons restore ventilation stabilize arterial blood gases. However, ability stimulate during OIRD has never been tested. We used optogenetic pharmacogenetic approaches, inhibit Phox2B / before after fentanyl administration. As expected, (500 µg/kg, ip) suppressed rate breathing. Before fentanyl, stimulation or chemogenetic inhibition cells increased decreased activity, respectively. Surprisingly, administration caused significantly greater increase activity compared pre-fentanyl levels. By contrast ablation profound instability fentanyl. results suggest does not within Thus, this study highlights potential stimulating as therapeutic approach function cases OIRD.

Language: Английский

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Peripheral opioid receptor antagonism alleviates fentanyl-induced cardiorespiratory depression and is devoid of aversive behavior

Published: March 17, 2025

Millions of Americans suffering from Opioid Use Disorders (OUD) face a high risk fatal overdose due to opioid-induced respiratory depression (OIRD). Fentanyl, powerful synthetic opioid, is major contributor the rising rates deaths. Reversing fentanyl overdoses has proved challenging its potency and rapid onset OIRD. We assessed contributions central peripheral mu opioid receptors (MORs) in mediating fentanyl-induced physiological responses. The peripherally restricted MOR antagonist naloxone methiodide (NLXM) both prevented reversed OIRD degree comparable that (NLX), indicating substantial involvement MORs Interestingly, NLXM-mediated reversal did not produce aversive behaviors observed after NLX. show neurons nucleus solitary tract (nTS), first synapse afferents, exhibit biphasic activity profile following exposure. NLXM pretreatment attenuates this activity, suggesting these responses are mediated by MORs. Together, findings establish critical role for MORs, including ascending inputs nTS, as sites dysfunction during Furthermore, selective antagonism could be promising therapeutic strategy managing sparing CNS-driven acute opioid-associated withdrawal aversion

Language: Английский

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Relax, but Don't Forget to Breathe: Ictal Central Apnea and SUDEP

Epiliepsy currents/Epilepsy currents, Journal Year: 2025, Volume and Issue: unknown

Published: April 30, 2025

Don't Forget to Breathe Liška K, Pant A, Jefferys JGR. Diaphragm relaxation causes seizure-related apnoeas in chronic and acute seizure models rats. Neurobiol Dis . 2024;203:106735. doi:10.1016/j.nbd.2024.106735 Background: Ictal central apnoea is a feature of focal temporal seizures. It implicated as risk factor for sudden unexpected death epilepsy (SUDEP). Here we study two different experimental seizures, one acute, adult genetically-unmodified rats, determine mechanisms apnoeas. Under general anaesthesia rats receive sensors nasal temperature, hippocampal and/or neocortical potentials, ECG or EMG subsequent tethered video-telemetry. Tetanus neurotoxin (TeNT), injected into hippocampus during surgery, induces epileptic focus. Other implanted intraperitoneal pentylenetetrazol (PTZ) evoke In chronically convulsive seizures cause (9.9 ± 5.3 s; 331 730 15 rats), associated with bradyarrhythmias. Absence EEG biomarkers exclude obstructive All eight TeNT-rats diaphragm have no evidence obstruction, EMGs significantly closer expiratory than inspiratory contraction pre-apnoeic respiration, which term “atonic diaphragm”. Consistent atonic that the airflow expiration, it human ictal apnoea. Two cases rat occur. One, telemetry end, reveals lethal apnoea, other only has video final days, cessation breathing shortly after last clonic movement. Telemetry following systemic PTZ repeated apnoeas, culminating apnoeas; are - 8 35 diaphragms initially contract tonically 8.5 15.0 s before relaxing, 27 remaining throughout terminal atonic. Differences types due (mainly atonic) mice (tonic) likely species-specific. Certain genetic mouse caused by tonic contraction, potentially expression epileptogenic mutations brain, including respiratory centres, contrast acquired epilepsies. We conclude TeNT model result from diaphragms. Relaxed could be particularly helpful therapeutic stimulation help restore respiration.

Language: Английский

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Putting back respiration into respiratory sinus arrhythmia or high-frequency heart rate variability: Implications for interpretation, respiratory rhythmicity, and health

Biological Psychology, Journal Year: 2023, Volume and Issue: 185, P. 108728 - 108728

Published: Dec. 11, 2023

Language: Английский

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Opioids, sleep, analgesia and respiratory depression: Their convergence on Mu (μ)-opioid receptors in the parabrachial area

Frontiers in Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: April 6, 2023

Opioids provide analgesia, as well modulate sleep and respiration, all by possibly acting on the μ-opioid receptors (MOR). MOR’s are ubiquitously present throughout brain, posing a challenge for understanding precise anatomical substrates that mediate opioid induced respiratory depression (OIRD) ultimately kills most users. Sleep is major modulator not only of pain perception, but also changing efficacy opioids analgesics. Therefore, disturbances risk factors developing overuse, withdrawal, poor treatment response pain, addiction relapse. Despite challenges to resolve neural malfunctions during overdose, two main areas, pre-Bötzinger complex (preBötC) in medulla parabrachial (PB) have been implicated regulating depression. More recent studies suggest it mediation PB causes OIRD. The act node upper brain stem receives input from chemosensory areas medulla, nociceptive information spinal cord. We previously shown neurons play an important role mediating arousal hypercapnia its projections forebrain centers, may relay stimuli. However, due heterogeneity cells PB, their roles regulating, sleep, depression, needs addressing. This review sheds light interactions between along with dissecting elements adversely affects respiration.

Language: Английский

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Fentanyl-Induced Respiratory Depression and Locomotor Hyperactivity Are Mediated by μ-Opioid Receptors Expressed in Somatostatin-Negative Neurons

eNeuro, Journal Year: 2023, Volume and Issue: 10(6), P. ENEURO.0035 - 23.2023

Published: June 1, 2023

Abstract Opioid drugs are widely used as analgesics but cause respiratory depression, a potentially lethal side effect with overdose, by acting on μ-opioid receptors (MORs) expressed in brainstem regions involved the control of breathing. Although many have been shown to regulate opioid-induced types neurons not identified. Somatostatin is major neuropeptide found circuits regulating breathing, it unknown whether somatostatin-expressing depression opioids. We examined coexpression Sst (gene encoding somatostatin) and Oprm1 MORs) mRNAs depression. Interestingly, mRNA expression was majority (>50%) -expressing cells preBötzinger Complex, nucleus tractus solitarius, ambiguus, Kölliker–Fuse nucleus. then compared responses fentanyl between wild-type full knock-out mice that lack MORs prevented rate from occurring. Next, using transgenic lacking functional specifically cells, we conditional mice. preserved when were deleted only cells. Our results show despite importance regulation these do mediate Instead, cell populations other than likely contribute effects fentanyl.

Language: Английский

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Experimental considerations for the assessment of in vivo and in vitro opioid pharmacology

Pharmacology & Therapeutics, Journal Year: 2021, Volume and Issue: 230, P. 107961 - 107961

Published: July 10, 2021

Language: Английский

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Nucleus Tractus Solitarius Neurons Activated by Hypercapnia and Hypoxia Lack Mu Opioid Receptor Expression

Frontiers in Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 15

Published: July 11, 2022

Impaired chemoreflex responses are a central feature of opioid-induced respiratory depression, however, the mechanism through which mu opioid receptor agonists lead to diminished chemoreflexes is not fully understood. One brainstem structure involved in impairment nucleus solitary tract (NTS), contains population neurons that express receptors. Here, we tested whether caudal NTS activated during challenge receptors and overlap with by opioids. Using genetic labeling receptor-expressing cFos immunohistochemistry as proxy for neuronal activation, examined distribution following hypercapnia, hypoxia, morphine administration. The main finding was hypoxia hypercapnia primarily did Furthermore, concurrent administration induced expression non-overlapping populations neurons. Together these results suggest an indirect effect opioids within NTS, could be mediated on afferents and/or inhibitory interneurons.

Language: Английский

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Current research in pathophysiology of opioid-induced respiratory depression, neonatal opioid withdrawal syndrome, and neonatal antidepressant exposure syndrome

Current Research in Toxicology, Journal Year: 2022, Volume and Issue: 3, P. 100078 - 100078

Published: Jan. 1, 2022

Respiratory depression (RD) is the primary cause of death due to opioids. Opioids bind mu (µ)-opioid receptors (MORs) encoded by MOR gene

Language: Английский

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A comparative examination of morphine and fentanyl: unravelling the differential impacts on breathing and airway stability

The Journal of Physiology, Journal Year: 2023, Volume and Issue: 601(20), P. 4625 - 4642

Published: Oct. 1, 2023

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

Language: Английский

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