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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Shared and unique genes and pathways between neuropathic and inflammatory pain assays

Brain Research, Journal Year: 2025, Volume and Issue: unknown, P. 149614 - 149614

Published: April 1, 2025

Language: Английский

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

Published: Dec. 10, 2024

Millions of Americans suffering from Opioid Use Disorders 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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Mu‐opioid receptors in tachykinin‐1‐positive cells mediate the respiratory and antinociceptive effects of the opioid fentanyl

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 6, 2024

Abstract Background and Purpose Opioid drugs are potent analgesics that carry the risk of respiratory side effects due to actions on μ ‐opioid receptors (MORs) in brainstem regions control respiration. Substance P is encoded by Tac1 gene expressed neurons regulating breathing, nociception, locomotion. Tac1‐ positive cells also express MORs mediating opioid‐induced depression. We determined role ‐positive opioid drugs. Experimental Approach In situ hybridization was used determine Oprm1 mRNA expression (gene encoding MORs) depression Conditional knockout mice lacking functional were produced locomotor responses analgesic fentanyl assessed using whole‐body plethysmography. A tail immersion assay assess antinociceptive response fentanyl. Key Results highly (>80%) subpopulations preBötzinger Complex, nucleus tractus solitarius, Kölliker–Fuse/lateral parabrachial region. Conditionally knocking out abolished rate, relative tidal volume, minute ventilation compared with mice. Importantly, eliminated cells, whereas induced preserved. Conclusions Implications Our findings suggest mediate depressive fentanyl, providing important insights for development pain therapies reduced effects.

Language: Английский

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Asymmetric neuromodulation in the respiratory network contributes to rhythm and pattern generation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 11, 2024

Like other brain circuits, the brainstem respiratory network is continually modulated by neurotransmitters that activate slow metabotropic receptors. In many cases, activation of these receptors only subtly modulates motor pattern. However, some receptor types evokes arrest pattern as can occur following µ-opioid We propose varied effects neuromodulation on depend neuromodulator expression and their influence excitability post-synaptic targets. Because a comprehensive characterization cellular properties across remains challenging, we test our hypothesis combining computational modelling with ensemble electrophysiologic recording in pre-Bötzinger complex (pre-BötC) using high-density multi-electrode arrays (MEA). Our model encapsulates neuromodulatory transmission organized asymmetrically to promote rhythm generation. To this hypothesis, increased strength connections used selective agonists

Language: Английский

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