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口服自行给药的呋喃基芬太尼和丙烯酰基芬太尼对小鼠的影响:抗伤害感受、依赖性和戒断反应以及对药物摄入的防御作用。

Effects of orally self-administered furanyl fentanyl and acryl fentanyl in mice: antinociception, dependence and withdrawal, and defense of consumption.

作者信息

Gannon Brenda M, Shepard Mary E, Pressley Justin M, Shaw Hannah E, Wolf Kayla J, Avram Marina, Moran Jeffery H, Fantegrossi William E

机构信息

Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Graduate School, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

Graduate School, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

出版信息

Neuropharmacology. 2025 Jun 12;278:110562. doi: 10.1016/j.neuropharm.2025.110562.

Abstract

Oral use of illicit fentanyl formulations is common, and these preparations may be contaminated with fentanyl analogs (FAs) with unknown pharmacological and toxicological properties. Route of administration impacts pharmacological effects, and pharmacokinetic or pharmacodynamic properties of oral fentanyl and FAs could influence aspects of opioid use disorder that are not necessarily present in animal models involving other routes of administration. We established oral consumption of water, or solutions of the FAs furanyl fentanyl and acryl fentanyl in C57 B l/6N mice. Consumption of pharmacologically-relevant concentrations of the FAs was reliably engendered, verified by induction of opioid-mediated antinociceptive effects in a warm-water tail withdrawal procedure, hypothermic effects, and observation of antagonist-precipitated withdrawal. When maintenance solutions were adulterated with the bitter tastant quinine, water control mice decreased their consumption, but mice consuming FA solutions defended their consumption, even at quinine concentrations that suppressed water drinking. Brief access to supplemental water, injection of the μ-opioid antagonist naltrexone, or administration of the μ-opioid agonist morphine all attenuated the defense of FA consumption. In all cases, the abuse-related effects of acryl fentanyl were greater than those of furanyl fentanyl. Consumption of acryl fentanyl also abolished weight gain across the study, and disrupted nest-building. The results of these experiments suggest that mice drinking furanyl fentanyl or acryl fentanyl experience opioid-mediated effects including antinociception, dependence and withdrawal, and abuse-related subjective effects, and provide proof of concept for use of this model to assess pharmacological and non-pharmacological manipulations which may attenuate the reinforcing effects of oral fentanyl and FAs.

摘要

非法芬太尼制剂的口服使用很常见,并且这些制剂可能被具有未知药理和毒理学特性的芬太尼类似物(FAs)污染。给药途径会影响药理作用,口服芬太尼和FAs的药代动力学或药效学特性可能会影响阿片类物质使用障碍的某些方面,而这些方面在涉及其他给药途径的动物模型中不一定存在。我们在C57 B l/6N小鼠中建立了口服水或FAs呋喃基芬太尼和丙烯酰基芬太尼溶液的模型。通过在温水甩尾试验中诱导阿片类药物介导的抗伤害感受作用、体温过低效应以及观察拮抗剂诱发的戒断反应,证实了小鼠能够可靠地摄入药理相关浓度的FAs。当维持溶液中掺入苦味剂奎宁时,饮水对照小鼠的饮水量减少,但摄入FA溶液的小鼠会维持其摄入量,即使在抑制饮水的奎宁浓度下也是如此。短暂补充水分、注射μ-阿片受体拮抗剂纳曲酮或给予μ-阿片受体激动剂吗啡均可减弱对FA摄入的维持。在所有情况下,丙烯酰基芬太尼的滥用相关效应均大于呋喃基芬太尼。在整个研究过程中,摄入丙烯酰基芬太尼还导致体重不再增加,并扰乱了筑巢行为。这些实验结果表明,饮用呋喃基芬太尼或丙烯酰基芬太尼的小鼠会经历阿片类药物介导的效应,包括抗伤害感受、依赖和戒断以及与滥用相关的主观效应,并为使用该模型评估可能减弱口服芬太尼和FAs强化作用的药理和非药理操作提供了概念验证。

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本文引用的文献

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