In vitro and in vivo study of butyrylfentanyl and 4-fluorobutyrylfentanyl in female and male mice: Role of the CRF1 receptor in cardiorespiratory impairment.

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY British Journal of Pharmacology Pub Date : 2024-10-04 DOI:10.1111/bph.17333
Sabrine Bilel, Joaquim Azevedo Neto, Micaela Tirri, Giorgia Corli, Marta Bassi, Anna Fantinati, Giovanni Serpelloni, Davide Malfacini, Claudio Trapella, Girolamo Calo', Matteo Marti
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Abstract

Background and purpose: Fentanyl analogues have been implicated in many cases of intoxication and death with overdose worldwide. The aim of this study is to investigate the pharmaco-toxicology of two fentanyl analogues: butyrylfentanyl (BUF) and 4-fluorobutyrylfentanyl (4F-BUF).

Experimental approach: In vitro, we measured agonist opioid receptor efficacy, potency, and selectivity and ability to promote interaction of the μ receptor with G protein and β-arrestin 2. In vivo, we evaluated thermal antinociception, stimulated motor activity and cardiorespiratory changes in female and male CD-1 mice injected with BUF or 4F-BUF (0.1-6 mg·kg-1). Opioid receptor specificity was investigated using naloxone (6 mg·kg-1). We investigated the possible role of stress in increasing cardiorespiratory toxicity using the corticotropin-releasing factor 1 (CRF1) antagonist antalarmin (10 mg·kg-1).

Key results: Agonists displayed the following rank of potency at μ receptors: fentanyl > 4F-BUF > BUF. Fentanyl and BUF behaved as partial agonists for the β-arrestin 2 pathway, whereas 4F-BUF did not promote β-arrestin 2 recruitment. In vivo, we revealed sex differences in motor and cardiorespiratory impairments but not antinociception induced by BUF and 4F-BUF. Antalarmin alone was effective in blocking respiratory impairment induced by BUF in both sexes but not 4F-BUF. The combination of naloxone and antalarmin significantly enhanced naloxone reversal of the cardiorespiratory impairments induced by BUF and 4F-BUF in mice.

Conclusion and implications: In this study, we have uncovered a novel mechanism by which synthetic opioids induce respiratory depression, shedding new light on the role of CRF1 receptors in cardiorespiratory impairments by μ agonists.

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丁酰芬太尼和4-氟丁酰芬太尼对雌性和雄性小鼠的体外和体内研究:CRF1受体在心肺功能损伤中的作用。
背景和目的:芬太尼类似物与全球许多中毒和用药过量死亡病例有牵连。本研究旨在探讨两种芬太尼类似物:丁酰芬太尼(BUF)和4-氟丁酰基芬太尼(4F-BUF)的药理毒理学:在体外,我们测量了激动剂阿片受体的功效、效力和选择性,以及促进μ受体与G蛋白和β-arrestin 2相互作用的能力;在体内,我们评估了雌性和雄性CD-1小鼠注射BUF或4F-BUF(0.1-6 mg-kg-1)后的热镇痛、刺激性运动活动和心肺功能变化。使用纳洛酮(6 mg-kg-1)对阿片受体特异性进行了研究。我们使用促肾上腺皮质激素释放因子 1(CRF1)拮抗剂安妥明(10 mg-kg-1)研究了应激在增加心肺毒性方面可能发挥的作用:激动剂对μ受体的效力排序如下:芬太尼 > 4F-BUF > BUF。芬太尼和BUF是β-阿司匹林2通路的部分激动剂,而4F-BUF并不促进β-阿司匹林2的招募。在体内,我们发现在 BUF 和 4F-BUF 诱导的运动和心肺功能损伤方面存在性别差异,但抗痛作用却不存在性别差异。单用安妥明能有效阻断 BUF 诱导的两性呼吸障碍,但不能阻断 4F-BUF 诱导的呼吸障碍。纳洛酮和安妥明联合使用可显著增强纳洛酮对 BUF 和 4F-BUF 诱导的小鼠心肺功能损伤的逆转作用:在这项研究中,我们发现了合成阿片类药物诱导呼吸抑制的一种新机制,为研究 CRF1 受体在μ激动剂所致心肺功能损害中的作用提供了新的线索。
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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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