CB1 Cannabinoid Receptor Agonists Induce Acute Respiratory Depression in Awake Mice

Pharmacological Research, Год журнала: 2025, Номер unknown, С. 107682 - 107682

Опубликована: Март 1, 2025

Recreational use of synthetic cannabinoid agonists (i.e., "spice compounds") that target the type 1 receptor (CB1) can cause acute respiratory failure in humans. However, Δ9-tetrahydrocannabinol (Δ9-THC), major psychoactive phytocannabinoid cannabis, is not traditionally thought to interact with brain system, based largely upon sparse labeling CB1 receptors medulla and relative safety suggested by widespread human use. Here we used whole body plethysmography RNAscope situ hybridization mice reconcile this conflict between conventional wisdom data. We examined effects full agonist CP55,940 Δ9-THC male female mice. potently dose-dependently suppressed minute ventilation tidal volume, decreasing measures effort peak inspiratory expiratory flow). Both cannabinoids reduced frequency, time while markedly increasing pause. Respiratory suppressive were fully blocked antagonist AM251, minimally impacted peripherally-restricted AM6545, occurred at doses lower than those produce cardinal behavioral signs activation. Using hybridization, also demonstrated extensive coexpression Cnr1 (encoding receptor) Oprm1 µ-opioid mRNA cells medullary pre-Bötzinger complex, a critical nucleus control. Our results show for present region essential breathing demonstrate suppression via activation central receptors.

Язык: Английский

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Opioid suppression of an excitatory pontomedullary respiratory circuit by convergent mechanisms

eLife, Год журнала: 2023, Номер 12

Опубликована: Июнь 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

Язык: Английский

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Opioids and obstructive sleep apnea

Journal of Clinical Sleep Medicine, Год журнала: 2021, Номер 18(2), С. 647 - 652

Опубликована: Окт. 22, 2021

Opioids are widely prescribed for pain management, and it is estimated that 40% of adults in the United States use prescription opioids every year. Opioid misuse leads to high mortality, with respiratory depression as main cause death. Animal human studies indicate opioid may lead sleep-disordered breathing. affect control breathing impair upper airway function, causing central apneas, obstruction, hypoxemia during sleep. The presence obstructive sleep apnea (OSA) increases risk opioid-induced depression. However, even if relationship between firmly established, question whether can aggravate OSA remains unanswered. While several reports have shown a prevalence nocturnal patients receiving dose opioids, other did not find correlation events. These differences be attributed considerable interindividual variability, divergent effects on different phenotypic traits OSA, wide-ranging methodology. This review will discuss mechanistic insights into hypoglossal motor activity association apnea.

Язык: Английский

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Oxycodone: A Current Perspective on Its Pharmacology, Abuse, and Pharmacotherapeutic Developments

Pharmacological Reviews, Год журнала: 2023, Номер 75(6), С. 1062 - 1118

Опубликована: Июнь 15, 2023

Oxycodone, a semisynthetic derivative of naturally occurring thebaine, an opioid alkaloid, has been available for more than 100 years. Although thebaine cannot be used therapeutically due to the occurrence convulsions at higher doses, it converted number other widely compounds that include naloxone, naltrexone, buprenorphine, and oxycodone. Despite early identification oxycodone, was not until 1990s clinical studies began explore its analgesic efficacy. These were followed by pursuit several preclinical examine effects abuse liability oxycodone in laboratory animals subjective human volunteers. For years forefront crisis, playing significant role contributing misuse abuse, with suggestions led transitioning opioids. Several concerns expressed as 1940s had potential similar heroin morphine. Both animal have confirmed, some cases amplified, these warnings. sharing structure morphine pharmacological actions also mediated μ-opioid receptor, there are differences pharmacology neurobiology The data emerged from many efforts analyze molecular mechanism generated considerable insight into actions, reviewed here, which, turn, provided new information on receptor pharmacology. SIGNIFICANCE STATEMENT: agonist, synthesized 1916 introduced use Germany 1917. It studied extensively therapeutic acute chronic neuropathic pain alternative Oxycodone drug widespread abuse. This article brings together integrated, detailed review recent advances identify analgesics without liability.

Язык: Английский

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Trends in Healthy Life Expectancy (HALE) and Disparities by Income and Region in Korea (2008–2020): Analysis of a Nationwide Claims Database

Journal of Korean Medical Science, Год журнала: 2024, Номер 39

Опубликована: Янв. 1, 2024

Healthy life expectancy is a well-recognized indicator for establishing health policy goals used in Korea's Health Plan. This study aimed to explore Koreans' healthy and its gender, income, regional disparities from 2008 2020.

Язык: Английский

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Opioids and pituitary function: expert opinion

Pituitary, Год журнала: 2022, Номер 25(1), С. 52 - 63

Опубликована: Янв. 23, 2022

Язык: 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, Год журнала: 2022, Номер 13

Опубликована: Май 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.

Язык: Английский

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Serotonin therapies for opioid-induced disordered swallow and respiratory depression

Journal of Applied Physiology, Год журнала: 2024, Номер 136(4), С. 821 - 843

Опубликована: Фев. 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

Язык: Английский

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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

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Global and regional burden of four drug use disorders in the elderly, 1990 to 2021: an analysis of the Global Burden of Disease Study

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Фев. 10, 2025

Background As the global population ages, burden of drug use disorders (DUDs) among elderly is rising. It imperative to conduct a quantitative analysis disease affecting this vulnerable population. Methods Utilize Global Burden Disease Study 2021 database obtain incidence rates and disability-adjusted life years (DALYs) for opioids, cocaine, amphetamines, cannabis (aged 60–89) across 204 countries 5 SDI regions from 1990 2021. Employ Joinpoint regression calculate average annual percentage change (AAPC) age-standardized (ASIR) DALYs (ASDR). Use Das Gupta method decompose analyze impacts changes in age structure, growth, epidemiology on during period. Finally, apply Bayesian Age-Period-Cohort (BAPC) model predict ASIR high-burden 2022 2035. Results Of four DUDs, opioids have highest burden. indicates that 2021, opioid disorder decreased with an AAPC -0.73 (95% CI: -0.79 0.67), while ASDR remained stable. Cocaine stable, but increased 0.94 0.77–1.11). The amphetamine generally stabilized. Geographic heterogeneity was evident at regional national levels, all DUDs increasing high-SDI areas remaining stable or declining other areas. High-income North America, represented by United States, shows higher disease. Decomposition growth main factor most regions, high-income America mainly affected epidemiological changes. According Predictive models, still rise, especially male group America. Conclusion varies countries, genders, underscoring need targeted public health policy adjustments strategic allocation medical resources mitigate

Язык: Английский

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