Antagonism of the antinociceptive effects of fentanyl and the veterinary anesthetic xylazine in mice

Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2025, Volume and Issue: 392(4), P. 103397 - 103397

Published: Feb. 5, 2025

A recent twist to the ongoing tragedy of opioid epidemic is adulteration fentanyl with veterinary tranquilizer xylazine, an α2-adrenoreceptor agonist. Unfortunately, our knowledge how and xylazine interact pharmacologically in different behavioral assays limited. We examined alone, 4 antagonists, multiple dose ratio combinations using a 52.5 °C hot-plate antinociception assay Swiss-Webster male female mice. Both produced full, dose-dependent increases antinociception. In antagonism studies, naltrexone blocked whereas yohimbine selective antagonist, idazoxan, antinociceptive effects xylazine. Naltrexone failed inhibit increased or decreased potency depending on dose. Haloperidol, D2/σ1 significantly shifted left. Overall, combining alter although when proportion was higher, less potent than alone. Either alone block 2.5X combination. However, either idazoxan combination suggesting that both noradrenergic receptors appear involved this conclusion, combined are dependent proportions coadministered antagonists may be required adulterated SIGNIFICANCE STATEMENT: Combinations agonist currently illicit drug market. The experiments described here examine pharmacology these drugs model mice better understand underlying receptor mechanisms for were predominantly simple agonism.

Language: Английский

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Xylazine potentiates the interoceptive effects of fentanyl in male and female rats

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

Published: Feb. 8, 2025

Abstract Rationale Xylazine, a sedative typically used in veterinary medicine, has been increasingly detected as an adulterant the unregulated opioid supply and present overdose deaths. Therefore, xylazine-adulterated fentanyl is growing public health concern. People who use drugs have reported that xylazine changes prolongs effects of Objectives We standard operant drug discrimination procedures to better understand how impacts discriminative stimulus/interoceptive fentanyl. Methods Male female Long-Evans rats (n=23) were trained discriminate (0.032 mg/kg intraperitoneal) such one lever was reinforced with sucrose on days when administered, other vehicle administered. Once met testing criteria, we tested dose range confirm stimulus control, then if alone produced fentanyl-like addition impacted interoceptive effects. Results Stimulus control confirmed, showed increased percent responses fentanyl-appropriate well decreased response rates for increasing doses Xylazine did not substitute but similar rate reductions alone. co-administered potentiated lower both males females reductions. Conclusions These results indicate enhances fentanyl, which may inform clinical research about

Language: Английский

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Xylazine as an emerging new psychoactive substance; focuses on both 5‐HT₇ and κ‐opioid receptors' molecular interactions and isosteric replacement

Archiv der Pharmazie, Journal Year: 2025, Volume and Issue: 358(3)

Published: March 1, 2025

Abstract Xylazine, traditionally used as a veterinary sedative, has recently emerged new psychoactive substance, being typically ingested in combination with fentanyl derivatives and hence raising significant public health concerns. Despite its increasing prevalence, little is known about molecular interactions human neuroreceptors, specifically the serotonin 7 (5‐HT R) kappa‐opioid (KOR) receptors, which play critical roles mood regulation, consciousness nociception. Hence, binding affinity of xylazine both 5‐HT R KOR through docking simulations dynamics calculations were investigated. These computational approaches revealed insights into receptor motifs highlighted structural modifications that could enhance affinity. The isosteric replacements within structure to improve efficacy assessed, demonstrating minimal can potentiate interaction KOR. findings may well advance our understanding xylazine's mechanism action, possibly contributing identifying suitable treatment/management treating xylazine‐related overdoses.

Language: Английский

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Fentanyl–Antibody Interaction as a Novel Strategy against Opiates and Opioids Abuse

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 3, 2025

While naloxone remains the antidote for opioid overdoses, more efficient tools are required to effectively combat this growing crisis. Vaccines and antibodies targeting substances of abuse appear be a novel promising approach tackling fentanyl epidemic. After an initial in-depth rundown on pharmacodynamics involved from structural mechanistic standpoint, brief overview pharmacological approaches used in clinical settings managing overdoses addiction, Perspective will mainly focused these innovative strategies, based development binding sequestering their generation vivo through vaccines. The most examined, production techniques potential applications, analyzing structures mechanisms antibody-substance interactions comparing with receptor processes.

Language: Английский

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Building Multidisciplinary Consensus on Inpatient Xylazine Management through Clinical Protocols

Substance Use &amp Addiction Journal, Journal Year: 2025, Volume and Issue: unknown

Published: April 15, 2025

The evolving unregulated drug supply in the United States has led to an unprecedented rise xylazine-adulterated synthetic opioid use-related morbidity and mortality, of which Pennsylvania shoulders a disproportionate burden. People experiencing these xylazine harms who seek acute medical care require complex clinical management, multidisciplinary coordination, appropriate linkage outpatient care. We describe our experience leading hospital-wide workgroup from February June 2024 collaboratively develop time-sensitive protocols on inpatient management patients exposed xylazine. Workgroup participants were organized into three subgroups: (1) toxicology screening harm reduction; (2) withdrawal management; (3) wound summarize implementation process protocol recommendations each subgroup highlight important cross-cutting issues related changing supply, standardized patient provider educational tools, next steps.

Language: Английский

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Exploring Human Misuse and Abuse of Veterinary Drugs: A Descriptive Pharmacovigilance Analysis Utilising the Food and Drug Administration’s Adverse Events Reporting System (FAERS)

Toxics, Journal Year: 2024, Volume and Issue: 12(11), P. 777 - 777

Published: Oct. 25, 2024

Evidence suggests an increasing misuse of veterinary medicines by humans. This study aims to analyse Adverse Events (AEs) associated with selected products using the Food and Drug Administration Reporting System (FAERS).

Language: Английский

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Implications of xylazine exposure in pregnancy: a narrative review

Journal of Addictive Diseases, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 8

Published: Aug. 21, 2024

The rise in pregnancy-related overdose deaths has been driven by the use of high-potency illicitly-manufactured synthetic opioids including fentanyl. Xylazine, a veterinary sedative, is increasingly noted as common adulterant United States illicit opioid supply. Exposure to xylazine-fentanyl combination associated with severe harms sedation, necrotic wounds, and symptoms xylazine withdrawal. Due limited data that directly addresses risks exposure during human pregnancy, we conducted narrative review summarize available evidence about clinical implications pregnancy drawing from animal models, general adult population, authors' experiences. Because presents unique pregnant persons, management related sequelae persons warrants nuanced management. Further, additional research critically needed develop best practice guidelines co-occurring xylazine-opioid harm reduction strategies reduce risk pregnancy.

Language: Английский

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Oral Fentanyl Consumption Alters Sleep Rhythms, Promotes Avoidance Behaviors, Impairs Fear Extinction Learning, and Alters Basolateral Amygdala Physiology in Male and Female Mice

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 29, 2023

Abstract The number of opioid overdose deaths has increased over the past several years, mainly driven by an increase in availability highly potent synthetic opioids, like fentanyl, un-regulated drug supply. Over last few changes supply, and particular counterfeit pills containing have made oral use opioids a more common route administration. Here, we used drinking dark (DiD) paradigm to model fentanyl self-administration using increasing concentrations male female mice 5 weeks. Fentanyl consumption peaked both at 30 µg/mL dose, with consuming significantly than mice. Mice consumed sufficient such that withdrawal was precipitated naloxone, males having symptoms, despite lower pharmacological exposure. We also performed behavioral assays measure avoidance behavior reward-seeking during abstinence. Female displayed reduced behaviors open field assay, whereas showed light/dark box assay. exhibited sucrose preference test. Fentanyl-consuming sexes impaired cued fear extinction learning following conditioning excitatory synaptic drive excitability BLA principal neurons. Our experiments demonstrate long-term results wide-ranging physiological disruptions. This could be useful further study syndrome neuroplasticity associated protracted withdrawal.

Language: Английский

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Oral Fentanyl Consumption and Withdrawal Impairs Fear Extinction Learning and Enhances Basolateral Amygdala Principal Neuron Excitatory-Inhibitory Balance in Male and Female Mice

Addiction Neuroscience, Journal Year: 2024, Volume and Issue: 13, P. 100182 - 100182

Published: Oct. 15, 2024

Language: Английский

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First Detection of Xylazine in Texas Wastewater and Its Association with Fentanyl Use

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

Published: Nov. 20, 2024

The United States is dealing with the drug overdose crisis that has intensified over past decade and compounded by emergence of new threats particularly xylazine, a veterinary sedative increasingly found in illicit supplies. This study investigates prevalence xylazine El Paso, Texas, U.S.-Mexico border city where its impact remains poorly understood. We employed wastewater analysis to detect examine potential correlation fentanyl use 14-month period (June 2023 July 2024). Our results show was detected samples from three four treatment plants serving city. heterogeneous, highest detection rate 29% observed one sewershed. All on xylazine-positive days also tested positive for norfentanyl, metabolite, demonstrating widespread consumption. Notably, sewersheds higher exhibited significantly loads, suggesting community-level association between two substances use. provides first evidence Texas highlights urgent need enhanced monitoring targeted public health interventions mitigate growing threat communities affected opioid crisis.

Language: Английский

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