In vitro and in vivo study of butyrylfentanyl and 4-fluorobutyrylfentanyl in female and male mice: Role of the CRF 1 receptor in cardiorespiratory impairment.
| Autor: | Bilel S; Section of Legal Medicine and LTTA Centre, Department of Translational Medicine, University of Ferrara, Ferrara, Italy., Azevedo Neto J; Section of Pharmacology, Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy., Tirri M; Section of Legal Medicine and LTTA Centre, Department of Translational Medicine, University of Ferrara, Ferrara, Italy., Corli G; Section of Legal Medicine and LTTA Centre, Department of Translational Medicine, University of Ferrara, Ferrara, Italy., Bassi M; Section of Legal Medicine and LTTA Centre, Department of Translational Medicine, University of Ferrara, Ferrara, Italy., Fantinati A; Department of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy., Serpelloni G; Neuroscience Clinical Center & TMS Unit, Verona, Italy.; Department of Psychiatry, College of Medicine, Drug Policy Institute, University of Florida, Gainesville, Florida, USA., Malfacini D; Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy., Trapella C; Department of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy., Calo' G; Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy., Marti M; Section of Legal Medicine and LTTA Centre, Department of Translational Medicine, University of Ferrara, Ferrara, Italy.; Center of Gender Medicine, University of Ferrara, Ferrara, Italy.; Collaborative Center of the National Early Warning System, Department for Anti-Drug Policies, Presidency of the Council of Ministers, Rome, Italy. |
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| Jazyk: | angličtina |
| Zdroj: | British journal of pharmacology [Br J Pharmacol] 2025 Jan; Vol. 182 (1), pp. 104-130. Date of Electronic Publication: 2024 Oct 04. |
| DOI: | 10.1111/bph.17333 |
| Abstrakt: | 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 (CRF 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 CRF (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.) |
| Databáze: | MEDLINE |
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