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

eNeuro, Год журнала: 2023, Номер 10(6), С. ENEURO.0035 - 23.2023

Опубликована: Июнь 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.

Язык: Английский

Fentanyl blockade of K+ channels contribute to Wooden Chest Syndrome

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 18, 2025

Abstract Fentanyl is a potent synthetic opioid widely used perioperatively and illicitly as drug of abuse 1,2 . It well established that fentanyl acts μ-opioid receptor agonist, signaling through Gα i/o intracellular pathways to inhibit electrical excitability, resulting in analgesia respiratory depression 3,4 However, uniquely also triggers muscle rigidity, including muscles, hindering the ability execute central commands or receive external resuscitation. This potentially lethal condition termed Wooden Chest Syndrome (WCS), mechanisms which are poorly understood 5–7 Here we show directly blocks subset EAG-class potassium channels 8 Our results demonstrate these expressed cervical spinal motoneurons, those innervating diaphragm. A significant fraction motoneurons excited by fentanyl, concomitant with blockade voltage-dependent non-inactivating K + currents In vivo electromyography revealed persistent tonic component diaphragmatic activity elicited but not morphine. Taken together our identify novel off-target mechanism for action, independent activation, paradoxical excitatory effect may underlie WCS. We anticipate findings inform design safer analgesics generalize other neuronal circuits implicated fentanyl-related maladaptive behaviors.

Язык: Английский

Functional Modulation of Retrotrapezoid Neurons Drives Fentanyl-Induced Respiratory Depression

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 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.

Язык: Английский

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

Опубликована: Март 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

Язык: Английский

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

Epiliepsy currents/Epilepsy currents, Год журнала: 2025, Номер unknown

Опубликована: Апрель 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.

Язык: Английский

Profiling human iPSC-derived sensory neurons for analgesic drug screening using a multi-electrode array

Cell Reports Methods, Год журнала: 2025, Номер unknown, С. 101051 - 101051

Опубликована: Май 1, 2025

Язык: Английский

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

Frontiers in Molecular Neuroscience, Год журнала: 2022, Номер 15

Опубликована: Июль 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.

Язык: Английский

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

Current Research in Toxicology, Год журнала: 2022, Номер 3, С. 100078 - 100078

Опубликована: Янв. 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

Язык: Английский

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

Frontiers in Neuroscience, Год журнала: 2023, Номер 17

Опубликована: Апрель 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.

Язык: Английский

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

Pharmacology & Therapeutics, Год журнала: 2021, Номер 230, С. 107961 - 107961

Опубликована: Июль 10, 2021

Язык: Английский