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

Authors :
Bilel, Sabrine
Azevedo Neto, Joaquim
Tirri, Micaela
Corli, Giorgia
Bassi, Marta
Fantinati, Anna
Serpelloni, Giovanni
Malfacini, Davide
Trapella, Claudio
Calo', Girolamo
Marti, Matteo
Source :
British Journal of Pharmacology; Jan2025, Vol. 182 Issue 1, p104-130, 27p
Publication Year :
2025

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00071188
Volume :
182
Issue :
1
Database :
Complementary Index
Journal :
British Journal of Pharmacology
Publication Type :
Academic Journal
Accession number :
181259306
Full Text :
https://doi.org/10.1111/bph.17333