Biased Agonism: Lessons from Studies of Opioid Receptor Agonists

The Annual Review of Pharmacology and Toxicology, Journal Year: 2022, Volume and Issue: 63(1), P. 491 - 515

Published: Sept. 28, 2022

In ligand bias different agonist drugs are thought to produce distinct signaling outputs when activating the same receptor. If these mediate therapeutic versus adverse drug effects, then agonists that selectively activate pathway would be extremely beneficial. It has long been μ-opioid receptor G protein– over β-arrestin-dependent pathways effective analgesia without effects such as respiratory depression. However, more recent data indicate most of and agonist-induced activation actually mediated by protein–dependent pathway, a number described protein biased in fact may not biased, but instead low-intrinsic-efficacy agonists. this review we discuss current state field at other opioid subtypes.

Language: Английский

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Mechanisms of opioid-induced respiratory depression

Archives of Toxicology, Journal Year: 2022, Volume and Issue: 96(8), P. 2247 - 2260

Published: April 26, 2022

Language: Английский

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Latent neural population dynamics underlying breathing, opioid-induced respiratory depression and gasping

Nature Neuroscience, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 5, 2024

Abstract Breathing is vital and must be concurrently robust flexible. This rhythmic behavior generated maintained within a rostrocaudally aligned set of medullary nuclei called the ventral respiratory column (VRC). The properties individual VRC are well known, yet technical challenges have limited interrogation entire population simultaneously. Here we characterize over 15,000 units using high-density electrophysiology, opto-tagging histological reconstruction. Population dynamics analysis reveals consistent rotational trajectories through low-dimensional neural manifold. These rotations even during opioid-induced depression. During severe hypoxia-induced gasping, reconfigure from to all-or-none, ballistic efforts. Thus, latent provide unifying lens onto activities large, heterogeneous populations neurons involved in simple, vital, breathing, describe how these respond variety perturbations.

Language: Английский

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Parabrachial tachykinin1-expressing neurons involved in state-dependent breathing control

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 21, 2023

Abstract Breathing is regulated automatically by neural circuits in the medulla to maintain homeostasis, but breathing also modified behavior and emotion. Mice have rapid patterns that are unique awake state distinct from those driven automatic reflexes. Activation of medullary neurons control does not reproduce these patterns. By manipulating transcriptionally defined parabrachial nucleus, we identify a subset express Tac1 , Calca gene exerts potent precise conditional awake, anesthetized, via projections ventral intermediate reticular zone medulla. Activating drives frequencies match physiological maximum through mechanisms differ underlie breathing. We postulate this circuit important for integration with state-dependent behaviors emotions.

Language: Английский

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Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms

eLife, Journal Year: 2023, Volume and Issue: 12

Published: June 14, 2023

Opioids depress breathing by inhibition of interconnected respiratory nuclei in the pons and medulla. Mu opioid receptor (MOR) agonists directly hyperpolarize a population neurons dorsolateral pons, particularly Kölliker-Fuse (KF) nucleus, that are key mediators opioid-induced depression. However, projection target synaptic connections MOR-expressing KF unknown. Here, we used retrograde labeling brain slice electrophysiology to determine project ventrolateral medulla, including preBötzinger complex (preBötC) rostral ventral group (rVRG). These medullary-projecting, pontine express FoxP2 distinct from calcitonin gene-related peptide-expressing lateral parabrachial neurons. Furthermore, release glutamate onto excitatory preBötC rVRG via monosynaptic projections, which is inhibited presynaptic receptors. Surprisingly, majority receiving MOR-sensitive glutamatergic input themselves hyperpolarized opioids, suggesting selective opioid-sensitive circuit inhibit this pontomedullary three mechanisms-somatodendritic MORs on medullary neuron terminals medulla-all could contribute

Language: Английский

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Anatomical distribution of µ-opioid receptors, neurokinin-1 receptors, and vesicular glutamate transporter 2 in the mouse brainstem respiratory network

Journal of Neurophysiology, Journal Year: 2024, Volume and Issue: 132(1), P. 108 - 129

Published: May 15, 2024

Opioid drugs can cause serious respiratory side-effects by binding to µ-opioid receptors (MORs) in brainstem regions that control breathing. To better understand the and their cellular subpopulations may be vulnerable modulation opioids, we provide a comprehensive map of Oprm1 (gene encoding MORs) mRNA expression throughout modulate Notably, identify glutamatergic neurokinin-1 receptor-expressing cells as potentially opioid worthy further investigation using targeted approaches.

Language: Английский

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S-Nitroso-L-Cysteine Stereoselectively Blunts the Deleterious Effects of Fentanyl on Breathing While Augmenting Antinociception in Freely-Moving Rats

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: May 26, 2022

Endogenous and exogenously administered S-nitrosothiols modulate the activities of central peripheral systems that control breathing. We have unpublished data showing deleterious effects morphine on arterial blood-gas chemistry (i.e., pH, pCO2, pO2, sO2) Alveolar-arterial gradient index gas exchange) were markedly diminished in anesthetized Sprague Dawley rats received a continuous intravenous infusion endogenous S-nitrosothiol, S-nitroso-L-cysteine. The present study extends these findings by unanesthetized adult male receiving an S-nitroso-L-cysteine (100 or 200 nmol/kg/min) ability injections potent synthetic opioid, fentanyl (10, 25, 50 μg/kg), to depress frequency breathing, tidal volume, minute ventilation. Our also found intravenously injected μg/kg) disturb eupneic which was measured as marked increase non-eupneic breathing index, substantially reduced infusions nmol/kg/min). In contrast, ventilation fully expressed (200 parent amino acid, L-cysteine, D-isomer, namely, S-nitroso-D-cysteine. addition, antinociceptive actions above doses monitored tail-flick latency assay, enhanced S-nitroso-L-cysteine, but not L-cysteine Taken together, add existing knowledge stereoselectively modulates detrimental opioids opens door for mechanistic studies designed establish whether pharmacological involve signaling processes include 1) activation plasma membrane ion channels receptors, 2) selective intracellular entry and/or 3) S-nitrosylation events. Whether alterations bioavailability bioactivity is key factor determining potency/efficacy intriguing question.

Language: Английский

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Serotonin therapies for opioid-induced disordered swallow and respiratory depression

Journal of Applied Physiology, Journal Year: 2024, Volume and Issue: 136(4), P. 821 - 843

Published: Feb. 22, 2024

Opioids are well-known to cause respiratory depression, but despite clinical evidence of dysphagia, the effects opioids on swallow excitability and motor pattern unknown. We tested clinically relevant opioid buprenorphine pharyngeal drive in male female rats. also evaluated utility 5-HT

Language: Английский

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Degenerate Neuronal and Circuit Mechanisms Important for Generating Rhythmic Motor Patterns

Physiological Reviews, Journal Year: 2024, Volume and Issue: 105(1), P. 95 - 135

Published: June 13, 2024

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

Language: Английский

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Fentanyl blockade of K+ channels contribute to Wooden Chest Syndrome

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

Published: Jan. 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.

Language: Английский

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