Assessment of abuse potential of furanylfentanyl and tetrahydrofuranylfentanyl.

IF 3.5 3区医学 Q2 NEUROSCIENCES

Psychopharmacology Pub Date : 2025-04-17 DOI:10.1007/s00213-025-06790-2

Yuanyuan Chen, Miaojun Lai, Xiangyu Li, Yanling Qiao, Deli Xu, Dan Fu, Bin Di, Peng Xu

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引用次数: 0

Abstract

Rational: Furanylfentanyl and tetrahydrofuranylfentanyl (THF-F) have been emerging in numerous intoxication and overdose cases in recent years. However, there remains a data deficiency regarding the abuse potential of these novel fentanyl analogs.

Objectives: This study was designed to systematically assess the abuse potential of furanylfentanyl and THF-F.

Methods: In this study, we evaluated the abuse potential of furanylfentanyl and THF-F via the conditioned place preference (CPP), drug self-administration, drug discrimination, and naloxone-precipitated withdrawal experiments with fentanyl as a reference.

Results: Results from CPP experiments indicated that furanylfentanyl and THF-F could induce CPP at minimum doses of 0.1 mg/kg and 3 mg/kg, respectively. These doses were 1 time and 30 times that of fentanyl (0.1 mg/kg). Furanylfentanyl elicited stable self-administration responses at 2.5 µg/kg/infusion, whereas THF-F did so at 50 µg/kg/infusion. In the drug-substitution test, furanylfentanyl and THF-F induced the maximum number of infusions at 1.10 µg/kg and 12.5 µg/kg, respectively, which were 1 time and 10 times that of fentanyl (1.21 µg/kg). In drug discrimination tests, all three substances were fully substituted for the discriminative-stimulus effects of heroin dose-dependently. The substitution potency of furanylfentanyl (ED₅₀ = 2.68 µg/kg) was similar to that of fentanyl (ED₅₀ = 2.66 µg/kg), while THF-F (ED₅₀ = 36.32 µg/kg) was 14-fold less potent than fentanyl. Repeated administration of furanylfentanyl and THF-F produced naloxone-precipitated withdrawal symptoms. Thus, furanylfentanyl exhibited comparable potency to fentanyl in terms of rewarding, reinforcing, and subjective effects, while THF-F had reduced potency in these effects. Both of them had physical dependence.

Conclusions: Taken together, our study presented new evidence indicating that furanylfentanyl and THF-F exhibit significant abuse potential in rodent models, which provides experimental data for the control. Furthermore, our study offered valuable information for future studies into the addictive properties of structurally modified fentanyl analogs.

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对呋喃基芬太尼和四氢呋喃基芬太尼滥用可能性的评估。

理性：近年来，呋喃基芬太尼和四氢呋喃基芬太尼（THF-F）在许多中毒和过量病例中出现。然而，关于这些新型芬太尼类似物的滥用潜力仍然存在数据不足。目的：本研究旨在系统评估呋喃芬太尼和四氢呋喃醚的滥用潜力。方法：本研究以芬太尼为参照，通过条件位置偏好（CPP）、自我给药、药物歧视和纳洛酮沉淀戒断实验，对呋喃尼芬太尼和四氢呋喃f- f的滥用潜力进行评价。结果：CPP实验结果表明，呋喃尼芬太尼和THF-F分别在最小剂量为0.1 mg/kg和3 mg/kg时可诱导CPP。这些剂量是芬太尼（0.1 mg/kg）的1倍和30倍。呋喃尼芬太尼在2.5µg/kg/次输注时引起稳定的自我给药反应，而THF-F在50µg/kg/次输注时引起稳定的自我给药反应。在药物替代试验中，呋喃基芬太尼和THF-F诱导的最大注射次数分别为1.10µg/kg和12.5µg/kg，分别是芬太尼（1.21µg/kg）的1倍和10倍。在药物鉴别试验中，这三种物质都完全取代了海洛因剂量依赖性的鉴别刺激效应。呋喃基芬太尼的取代效能（ED50 = 2.68µg/kg）与芬太尼（ED50 = 2.66µg/kg）相似，而THF-F （ED50 = 36.32µg/kg）的取代效能比芬太尼低14倍。反复给药呋喃尼芬太尼和四氢呋喃f产生纳洛酮沉淀戒断症状。因此，呋喃基芬太尼在奖励、强化和主观效应方面表现出与芬太尼相当的效力，而THF-F在这些作用中的效力较低。他们俩都有身体依赖。结论：综上所述，我们的研究提供了新的证据，表明呋喃尼芬太尼和四氢呋喃f在啮齿动物模型中具有明显的滥用潜力，为对照提供了实验数据。此外，我们的研究为未来研究结构修饰的芬太尼类似物的成瘾性提供了有价值的信息。

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来源期刊

Psychopharmacology 医学-精神病学

CiteScore

7.10

自引率

5.90%

发文量

257

审稿时长

2-4 weeks

期刊介绍： Official Journal of the European Behavioural Pharmacology Society (EBPS) Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields: Human Psychopharmacology: Experimental This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered. Human Psychopharmacology: Clinical and Translational This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects. Preclinical psychopharmacology: Behavioral and Neural This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels. Preclinical Psychopharmacology: Translational This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways. Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.