In vitro and in vivo study of butyrylfentanyl and 4-fluorobutyrylfentanyl in female and male mice: Role of the CRF
4‐fluorobutyrylfentanyl
CRF1
antalarmin
butyrylfentanyl
fentanyl
mu opioid receptor
naloxone
novel psychoactive substances
respiratory depression
β‐arrestin 2
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
04 Oct 2024
04 Oct 2024
Historique:
revised:
03
07
2024
received:
04
01
2024
accepted:
29
07
2024
medline:
5
10
2024
pubmed:
5
10
2024
entrez:
5
10
2024
Statut:
aheadofprint
Résumé
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). 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 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. In this study, we have uncovered a novel mechanism by which synthetic opioids induce respiratory depression, shedding new light on the role of CRF
Sections du résumé
BACKGROUND AND PURPOSE
OBJECTIVE
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
METHODS
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
KEY RESULTS
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
CONCLUSIONS
In this study, we have uncovered a novel mechanism by which synthetic opioids induce respiratory depression, shedding new light on the role of CRF
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Department for Anti-Drug Policies, Presidency of the Council of Ministers
Organisme : Università degli Studi di Ferrara
ID : FAR 2021
Organisme : Università degli Studi di Ferrara
ID : FAR 2022
Organisme : Università degli Studi di Padova
ID : DOR 2021/22
Informations de copyright
© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
Références
Alexander, S. P. H., Christopoulos, A., Davenport, A. P., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Abbracchio, M. P., Abraham, G., Agoulnik, A., Alexander, W., Al‐Hosaini, K., Bäck, M., Baker, J. G., Barnes, N. M., … Ye, R. D. (2023). The Concise Guide to PHARMACOLOGY 2023/24: G protein‐coupled receptors. British Journal of Pharmacology, 180, S23–S144. https://doi.org/10.1111/bph.16177
Alexander, S. P. H., Fabbro, D., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Annett, S., Boison, D., Burns, K. E., Dessauer, C., Gertsch, J., Helsby, N. A., Izzo, A. A., Ostrom, R., Papapetropoulos, A., … Wong, S. S. (2023). The concise guide to PHARMACOLOGY 2023/24: Enzymes. British Journal of Pharmacology, 180, S289–S373. https://doi.org/10.1111/bph.16181
Algera, M. H., Kamp, J., van der Schrier, R., van Velzen, M., Niesters, M., Aarts, L., Dahan, A., & Olofsen, E. (2019). Opioid‐induced respiratory depression in humans: A review of pharmacokinetic‐pharmacodynamic modelling of reversal. British Journal of Anaesthesia, 122(6), e168–e179. https://doi.org/10.1016/j.bja.2018.12.023
Amaducci, A., Aldy, K., Campleman, S. L., Li, S., Meyn, A., Abston, S., Culbreth, R. E., Krotulski, A., Logan, B., Wax, P., Brent, J., Manini, A. F., & Toxicology Investigators Consortium Fentalog Study Group. (2023). Naloxone Use in Novel Potent Opioid and Fentanyl Overdoses in Emergency Department Patients. JAMA Network Open, 6(8), e2331264. https://doi.org/10.1001/jamanetworkopen.2023.31264
Bäckberg, M., Beck, O., Jönsson, K. H., & Helander, A. (2015). Opioid intoxications involving butyrfentanyl, 4‐fluorobutyrfentanyl, and fentanyl from the Swedish STRIDA project. Clinical Toxicology, 53(7), 609–617. https://doi.org/10.3109/15563650.2015.1054505
Barbosa‐Leiker, C., Campbell, A. N. C., McHugh, R. K., Guille, C., & Greenfield, S. F. (2021). Opioid use disorder in women and the implications for treatment. Psychiatric Research and Clinical Practice, 3(1), 3–11. https://doi.org/10.1176/appi.prcp.2019005
Bilel, S., Azevedo, N. J., Arfè, R., Tirri, M., Gregori, A., Serpelloni, G., De‐Giorgio, F., Frisoni, P., Neri, M., Calò, G., & Marti, M. (2020). In vitro and in vivo pharmacological characterization of the synthetic opioid MT‐45. Neuropharmacology, 171, 108110. https://doi.org/10.1016/j.neuropharm.2020.108110
Bilel, S., Azevedo Neto, J., Arfè, R., Tirri, M., Gaudio, R. M., Fantinati, A., Bernardi, T., Boccuto, F., Marchetti, B., Corli, G., Serpelloni, G., De‐Giorgio, F., Malfacini, D., Trapella, C., Calo', G., & Marti, M. (2022). In vitro and in vivo pharmaco‐dynamic study of the novel fentanyl derivatives: Acrylfentanyl, ocfentanyl and furanylfentanyl. Neuropharmacology, 209, 109020. https://doi.org/10.1016/j.neuropharm.2022.109020
Bilel, S., Murari, M., Pesavento, S., Arfè, R., Tirri, M., Torroni, L., Marti, M., Tagliaro, F., & Gottardo, R. (2023). Toxicity and behavioural effects of ocfentanil and 2‐furanylfentanyl in zebrafish larvae and mice. Neurotoxicology, 95, 83–93. https://doi.org/10.1016/j.neuro.2023.01.003
Broadbear, J. H., Winger, G., Rivier, J. E., Rice, K. C., & Woods, J. H. (2004). Corticotropin‐releasing hormone antagonists, astressin B and antalarmin: Differing profiles of activity in rhesus monkeys. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 29(6), 1112–1121. https://doi.org/10.1038/sj.npp.1300410
Butelman, E. R., Huang, Y., Epstein, D. H., Shaham, Y., Goldstein, R. Z., Volkow, N. D., & Alia‐Klein, N. (2023). Overdose mortality rates for opioids and stimulant drugs are substantially higher in men than in women: state‐level analysis. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 48(11), 1639–1647. https://doi.org/10.1038/s41386-023-01601-8
Camarda, V., & Calo, G. (2013). Chimeric G proteins in fluorimetric calcium assays: Experience with opioid receptors. Methods in Molecular Biology, 937, 293–Methods in Molecular Biology. https://doi.org/10.1007/978-1-62703-086-1_18
Chorvat, R. J., Corman, M. L., Breslin, M. J., Collins, J. T., Faraci, S., MacCoss, M., Dunaiskis, A. R., Fan, K. H., Schmidt, A. W., & Seymour, P. A. (1999). Cp‐154,526: a potent and selective non‐peptide antagonist of the corticotropin‐releasing factor 1 (CRF1) receptor. Journal of Medicinal Chemistry, 42(1), 135–138. https://doi.org/10.1021/jm980563h
Curtis, M. J., Alexander, S. P. H., Cirino, G., George, C. H., Kendall, D. A., Insel, P. A., Izzo, A. A., Ji, Y., Panettieri, R. A., Patel, H. H., Sobey, C. G., Stanford, S. C., Stanley, P., Stefanska, B., Stephens, G. J., Teixeira, M. M., Vergnolle, N., & Ahluwalia, A. (2022). Planning experiments: Updated guidance on experimental design and analysis and their reporting III. British Journal of Pharmacology, 179(15), 3907–3913. https://doi.org/10.1111/bph.15868
Deak, T., Nguyen, K. T., Ehrlich, A. L., Watkins, L. R., Spencer, R. L., Maier, S. F., Licinio, J., Wong, M. L., Chrousos, G. P., Webster, E., & Gold, P. W. (1999). The impact of the nonpeptide corticotropin‐releasing hormone antagonist antalarmin on behavioral and endocrine responses to stress. Endocrinology, 140(1), 79–86. https://doi.org/10.1210/endo.140.1.6415
Di Chiara, G., & Imperato, A. (1988). Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proceedings of the National Academy of Sciences of the United States of America, 85(14), 5274–5278. https://doi.org/10.1073/pnas.85.14.5274
Di Francesco, G., Montesano, C., Vincenti, F., Bilel, S., Corli, G., Petrella, G., Cicero, D. O., Gregori, A., Marti, M., & Sergi, M. (2024). Tackling new psychoactive substances through metabolomics: UHPLC‐HRMS study on natural and synthetic opioids in male and female murine models. Scientific Reports, 14(1), 9432. https://doi.org/10.1038/s41598-024-60045-2
Drug Enforcement Administration, Department of Justice. (2016). Schedules of controlled substances: Temporary placement of butyryl fentanyl and beta‐hydroxythiofentanyl into schedule I. Final order. Federal Register, 81, 29492–29496.
Ducottet, C., Griebel, G., & Belzung, C. (2003). Effects of the selective nonpeptide corticotropin‐releasing factor receptor 1 antagonist antalarmin in the chronic mild stress model of depression in mice. Progress in Neuro‐Psychopharmacology & Biological Psychiatry, 27(4), 625–631. https://doi.org/10.1016/S0278-5846(03)00051-4
Eshleman, A. J., Nagarajan, S., Wolfrum, K. M., Reed, J. F., Nilsen, A., Torralva, R., & Janowsky, A. (2020). Affinity, potency, efficacy, selectivity, and molecular modeling of substituted fentanyls at opioid receptors. Biochemical Pharmacology, 182, 114293. https://doi.org/10.1016/j.bcp.2020.114293
Esposito, P., Basu, S., Letourneau, R., Jacobson, S., & Theoharides, T. C. (2003). Corticotropin‐releasing factor (CRF) can directly affect brain microvessel endothelial cells. Brain Research, 968(2), 192–198. https://doi.org/10.1016/s0006-8993(03)02237-6
European Monitoring Centre for Drugs and Drug Addiction, 2015. European drug report 2015: Trends and developments. Publications Office of the European Union. https://www.emcdda.europa.eu/publications/edr/trends‐developments/2015_en
European Monitoring Centre for Drugs and Drug Addiction, 2022. European drug report 2022: Trends and developments. Publications Office of the European Union. https://www.emcdda.europa.eu/publications/edr/trends‐developments/2022_en
Fattore, L., Marti, M., Mostallino, R., & Castelli, M. P. (2020). Sex and gender differences in the effects of novel psychoactive substances. Brain Sciences, 10(9), 606. https://doi.org/10.3390/brainsci10090606
Fernandez, S. P., Broussot, L., Marti, F., Contesse, T., Mouska, X., Soiza‐Reilly, M., Marie, H., Faure, P., & Barik, J. (2018). Mesopontine cholinergic inputs to midbrain dopamine neurons drive stress‐induced depressive‐like behaviors. Nature Communications, 9(1), 4449. https://doi.org/10.1038/s41467-018-06809-7
Girardot, M. N., & Holloway, F. A. (1984). Intermittent cold water stress‐analgesia in rats: Cross‐tolerance to morphine. Pharmacology, Biochemistry, and Behavior, 20(4), 631–633. https://doi.org/10.1016/0091-3057(84)90315-0
Glatfelter, G. C., Vandeputte, M. M., Chen, L., Walther, D., Tsai, M. M., Shi, L., Stove, C. P., & Baumann, M. H. (2023). Alkoxy chain length governs the potency of 2‐benzylbenzimidazole ‘nitazene’ opioids associated with human overdose. Psychopharmacology, 240(12), 2573–2584. https://doi.org/10.1007/s00213-023-06451-2
Guajardo, H. M., & Valentino, R. J. (2021). Sex differences in μ‐opioid regulation of coerulear‐cortical transmission. Neuroscience Letters, 746, 135651. https://doi.org/10.1016/j.neulet.2021.135651
Habib, K. E., Weld, K. P., Rice, K. C., Pushkas, J., Champoux, M., Listwak, S., Webster, E. L., Atkinson, A. J., Schulkin, J., Contoreggi, C., Chrousos, G. P., McCann, S. M., Suomi, S. J., Higley, J. D., & Gold, P. W. (2000). Oral administration of a corticotropin‐releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates. Proceedings of the National Academy of Sciences of the United States of America, 97(11), 6079–6084. https://doi.org/10.1073/pnas.97.11.6079
Haile, C. N., Baker, M. D., Sanchez, S. A., Lopez Arteaga, C. A., Duddupudi, A. L., Cuny, G. D., Norton, E. B., Kosten, T. R., & Kosten, T. A. (2022). An immunconjugate vaccine alters distribution and reduces the antinociceptive, behavioral and physiological effects of fentanyl in male and female rats. Pharmaceutics, 14(11), 2290. https://doi.org/10.3390/pharmaceutics14112290
Haouzi, P., & Tubbs, N. (2022). Effects of fentanyl overdose‐induced muscle rigidity and dexmedetomidine on respiratory mechanics and pulmonary gas exchange in sedated rats. Journal of Applied Physiology, 132(6), 1407–1422. https://doi.org/10.1152/japplphysiol.00819.2021
Heinrichs, S. C., Menzaghi, F., Schulteis, G., Koob, G. F., & Stinus, L. (1995). Suppression of corticotropin‐releasing factor in the amygdala attenuates aversive consequences of morphine withdrawal. Behavioural Pharmacology, 6(1), 74–80. https://doi.org/10.1097/00008877-199501000-00011
Hsin, L., Tian, X., Webster, E., Coop, A., Caldwell, T., Jacobson, A., Chrousos, G., Gold, P., Habib, K., Ayala, A., Eckelman, W., Contoreggi, C., & Rice, K. (2002). CRHR1 Receptor binding and lipophilicity of pyrrolopyrimidines, potential nonpeptide corticotropin‐releasing hormone type 1 receptor antagonists. Bioorganic and Medicinal Chemistry, 10(1), 175–183. https://doi.org/10.1016/s0968-0896(01)00261-9
Kaplovitch, E., Gomes, T., Camacho, X., Dhalla, I. A., Mamdani, M. M., & Juurlink, D. N. (2015). Sex differences in dose escalation and overdose death during chronic opioid therapy: A population‐based cohort study. PLoS ONE, 10(8), e0134550. https://doi.org/10.1371/journal.pone.0134550
Kenakin, T. (2004). A pharmacology primer. Elsevier Academic Press.
Krantz, M. J., Palmer, R. B., & Haigney, M. C. P. (2021). Cardiovascular complications of opioid use: JACC state‐of‐the‐art review. Journal of the American College of Cardiology, 77(2), 205–223. https://doi.org/10.1016/j.jacc.2020.11.002
Lilley, E., Stanford, S. C., Kendall, D. E., Alexander, S. P., Cirino, G., Docherty, J. R., George, C. H., Insel, P. A., Izzo, A. A., Ji, Y., Panettieri, R. A., Sobey, C. G., Stefanska, B., Stephens, G., Teixeira, M., & Ahluwalia, A. (2020). ARRIVE 2.0 and the British Journal of Pharmacology: Updated guidance for 2020. British Journal of Pharmacology, 177(16), 3611–3616. https://doi.org/10.1111/bph.15178
Little, K. M., & Kosten, T. A. (2023). Focus on fentanyl in females: Sex and gender differences in the physiological and behavioral effects of fentanyl. Frontiers in Neuroendocrinology, 71, 101096. https://doi.org/10.1016/j.yfrne.2023.101096
Lui, P. W., Lee, T. Y., & Chan, S. H. (1990). Involvement of coerulospinal noradrenergic pathway in fentanyl‐induced muscular rigidity in rats. Neuroscience Letters, 108(1–2), 183–188. https://doi.org/10.1016/0304-3940(90)90728-r
Malcolm, N. J., Palkovic, B., Sprague, D. J., Calkins, M. M., Lanham, J. K., Halberstadt, A. L., Stucke, A. G., & McCorvy, J. D. (2023). Mu‐opioid receptor selective superagonists produce prolonged respiratory depression. iScience, 26(7), 107121. https://doi.org/10.1016/j.isci.2023.107121
Malfacini, D., Ambrosio, C., Gro', M. C., Sbraccia, M., Trapella, C., Guerrini, R., Bonora, M., Pinton, P., Costa, T., & Calo', G. (2015). Pharmacological profile of nociceptin/orphanin FQ receptors interacting with G‐proteins and β‐arrestins 2. PLoS ONE, 10(8), e0132865. https://doi.org/10.1371/journal.pone.0132865
Marchette, R. C. N., Carlson, E. R., Frye, E. V., Hastings, L. E., Vendruscolo, J. C. M., Mejias‐Torres, G., Lewis, S. J., Hampson, A., Volkow, N. D., Vendruscolo, L. F., & Koob, G. F. (2023). Heroin‐ and fentanyl‐induced respiratory depression in a rat plethysmography model: Potency, tolerance, and sex differences. The Journal of Pharmacology and Experimental Therapeutics, 385(2), 117–134. https://doi.org/10.1124/jpet.122.001476
Matsui, A., Jarvie, B. C., Robinson, B. G., Hentges, S. T., & Williams, J. T. (2014). Separate GABA afferents to dopamine neurons mediate acute action of opioids, development of tolerance, and expression of withdrawal. Neuron, 82(6), 1346–1356. https://doi.org/10.1016/j.neuron.2014.04.030
Molinari, P., Vezzi, V., Sbraccia, M., Grò, C., Riitano, D., Ambrosio, C., Casella, I., & Costa, T. (2010). Morphine‐like opiates selectively antagonize receptor‐arrestin interactions. The Journal of Biological Chemistry, 285(17), 12522–12535. https://doi.org/10.1074/jbc.M109.059410
Papaleo, F., Kitchener, P., & Contarino, A. (2007). Disruption of the CRF/CRF1 receptor stress system exacerbates the somatic signs of opiate withdrawal. Neuron, 53(4), 577–589. https://doi.org/10.1016/j.neuron.2007.01.022
Peckham, E. M., & Traynor, J. R. (2006). Comparison of the antinociceptive response to morphine and morphine‐like compounds in male and female Sprague‐Dawley rats. The Journal of Pharmacology and Experimental Therapeutics, 316(3), 1195–1201. https://doi.org/10.1124/jpet.105.094276
Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., Avey, M. T., Baker, M., Browne, W. J., Clark, A., Cuthill, I. C., Dirnagl, U., Emerson, M., Garner, P., Holgate, S. T., Howells, D. W., Karp, N. A., Lazic, S. E., Lidster, K., MacCallum, C. J., Macleod, M., … Würbel, H. (2020). The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biology, 18(7), e3000410. https://doi.org/10.1371/journal.pbio.3000410
Pintér, D., Balangó, B., Simon, B., Palotai, M., Csabafi, K., Dobó, É., Ibos, K. E., & Bagosi, Z. (2021). The effects of CRF and the urocortins on the hippocampal acetylcholine release in rats. Neuropeptides, 88, 102147. https://doi.org/10.1016/j.npep.2021.102147
Ramos‐Gonzalez, N., Groom, S., Sutcliffe, K. J., Bancroft, S., Bailey, C. P., Sessions, R. B., Henderson, G., & Kelly, E. (2023). Carfentanil is a β‐arrestin‐biased agonist at the μ opioid receptor. British Journal of Pharmacology, 180(18), 2341–2360. https://doi.org/10.1111/bph.16084
Reyes, B. A., Glaser, J. D., & Van Bockstaele, E. J. (2007). Ultrastructural evidence for co‐localization of corticotropin‐releasing factor receptor and μ‐opioid receptor in the rat nucleus locus coeruleus. Neuroscience Letters, 413(3), 216–221. https://doi.org/10.1016/j.neulet.2006.11.069
Richeval, C., Baillieux, M., Pawlak, G., Phanithavong, M., Wiart, J.‐f., Humbert, L., Batisse, A., Lamoureux, C., Pfau, G., Nefau, T., Allorge, D., & Gaulier, J.‐M. (2019). Benzoylfentanyl and parafluorobutyrfentanyl: Some analytical and metabolism data. Toxicologie Analytique et Clinique, 31, 258–267. https://doi.org/10.1016/j.toxac.2019.01.004
Rodgers, R. J., & Randall, J. I. (1985). Social conflict analgesia: Studies on naloxone antagonism and morphine cross‐tolerance in male DBA/2 mice. Pharmacology, Biochemistry, and Behavior, 23(5), 883–887. https://doi.org/10.1016/0091-3057(85)90087-5
Rzasa Lynn, R., & Galinkin, J. L. (2018). Naloxone dosage for opioid reversal: Current evidence and clinical implications. Therapeutic Advances in Drug Safety, 9(1), 63–88.
Sauvage, M., & Steckler, T. (2001). Detection of corticotropin‐releasing hormone receptor 1 immunoreactivity in cholinergic, dopaminergic and noradrenergic neurons of the murine basal forebrain and brainstem nuclei—Potential implication for arousal and attention. Neuroscience, 104(3), 643–652. https://doi.org/10.1016/s0306-4522(01)00137-3
Schwienteck, K. L., Faunce, K. E., Rice, K. C., Obeng, S., Zhang, Y., Blough, B. E., Grim, T. W., Negus, S. S., & Banks, M. L. (2019). Effectiveness comparisons of G‐protein biased and unbiased mu opioid receptor ligands in warm water tail‐withdrawal and drug discrimination in male and female rats. Neuropharmacology, 150, 200–209. https://doi.org/10.1016/j.neuropharm.2019.01.020
Seymour, P. A., Schmidt, A. W., & Schulz, D. W. (2003). The pharmacology of CP‐154,526, a non‐peptide antagonist of the CRH1 receptor: A review. CNS Drug Reviews, 9(1), 57–96. https://doi.org/10.1111/j.1527-3458.2003.tb00244.x
Shaham, Y., Erb, S., Leung, S., Buczek, Y., & Stewart, J. (1998). CP‐154,526, a selective, non‐peptide antagonist of the corticotropin‐releasing factor1 receptor attenuates stress‐induced relapse to drug seeking in cocaine‐ and heroin‐trained rats. Psychopharmacology, 137(2), 184–190. https://doi.org/10.1007/s002130050608
Sharp, J. L., Pearson, T., & Smith, M. A. (2022). Sex differences in opioid receptor mediated effects: Role of androgens. Neuroscience and Biobehavioral Reviews, 134, 104522. https://doi.org/10.1016/j.neubiorev.2022.104522
Staeheli, S. N., Baumgartner, M. R., Gauthier, S., Gascho, D., Jarmer, J., Kraemer, T., & Steuer, A. E. (2016). Time‐dependent postmortem redistribution of butyrfentanyl and its metabolites in blood and alternative matrices in a case of butyrfentanyl intoxication. Forensic Science International, 266, 170–177. https://doi.org/10.1016/j.forsciint.2016.05.034
Steidl, S., Wasserman, D. I., Blaha, C. D., & Yeomans, J. S. (2017). Opioid‐induced rewards, locomotion, and dopamine activation: A proposed model for control by mesopontine and rostromedial tegmental neurons. Neuroscience and Biobehavioral Reviews, 83, 72–82. https://doi.org/10.1016/j.neubiorev.2017.09.022
Stinus, L., Cador, M., Zorrilla, E. P., & Koob, G. F. (2005). Buprenorphine and a CRF1 antagonist block the acquisition of opiate withdrawal‐induced conditioned place aversion in rats. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 30(1), 90–98. https://doi.org/10.1038/sj.npp.1300487
Torralva, R., & Janowsky, A. (2019). Noradrenergic mechanisms in fentanyl‐mediated rapid death explain failure of naloxone in the opioid crisis. The Journal of Pharmacology and Experimental Therapeutics, 371(2), 453–475. https://doi.org/10.1124/jpet.119.258566
Towers, E. B., Setaro, B., & Lynch, W. J. (2022). Sex‐ and dose‐dependent differences in the development of an addiction‐like phenotype following extended‐access fentanyl self‐administration. Frontiers in Pharmacology, 13, 841873. https://doi.org/10.3389/fphar.2022.841873
Tsai, M. M., Chen, L., Baumann, M. H., Canals, M., Javitch, J. A., Lane, J. R., & Shi, L. (2023). The in vitro functional profiles of fentanyl and nitazene analogs at the μ‐opioid receptor—High efficacy is dangerous regardless of signaling bias. bioRxiv, 2023.11.10.566672. https://doi.org/10.1101/2023.11.10.566672
United Nations Office on Drugs and Crime. (2023). World drug report: Executive summary.
Vachon, L., Costa, T., & Herz, A. (1987). Opioid receptor desensitization in NG 108‐15 cells: Differential effects of a full and a partial agonist on the opioid‐dependent GTPase. Biochemical Pharmacology, 36(18), 2889–2897. https://doi.org/10.1016/0006-2952(87)90199-7
Vandeputte, M. M., Van Uytfanghe, K., Layle, N. K., St Germaine, D. M., Iula, D. M., & Stove, C. P. (2021). Synthesis, chemical characterization, and μ‐opioid receptor activity assessment of the emerging group of “nitazene” 2‐benzylbenzimidazole synthetic opioids. ACS Chemical Neuroscience, 12(7), 1241–1251. https://doi.org/10.1021/acschemneuro.1c00064
VanHouten, J. P., Rudd, R. A., Ballesteros, M. F., & Karin, A. (2019). Mack: Drug overdose deaths among women aged 30–64 years—United States, 1999–2017. MMWR. Morbidity and Mortality Weekly Report, 68(1), 1–5. https://doi.org/10.15585/mmwr.mm6801a1
Varshneya, N. B., Hassanien, S. H., Holt, M. C., Stevens, D. L., Layle, N. K., Bassman, J. R., Iula, D. M., & Beardsley, P. M. (2022). Respiratory depressant effects of fentanyl analogs are opioid receptor‐mediated. Biochemical Pharmacology, 195, 114805. https://doi.org/10.1016/j.bcp.2021.114805
Varshneya, N. B., Hassanien, S. H., Holt, M. C., Stevens, D. L., Layle, N. K., Bassman, J. R., Iula, D. M., & Beardsley, P. M. (2023). Fentanyl analog structure‐activity relationships demonstrate determinants of diverging potencies for antinociception and respiratory depression. Pharmacology, Biochemistry, and Behavior, 226, 173572. https://doi.org/10.1016/j.pbb.2023.173572
Varshneya, N. B., Walentiny, D. M., Moisa, L. T., Walker, T. D., Akinfiresoye, L. R., & Beardsley, P. M. (2019). Opioid‐like antinociceptive and locomotor effects of emerging fentanyl‐related substances. Neuropharmacology, 151, 171–179. https://doi.org/10.1016/j.neuropharm.2019.03.023
World Health Organization. (2017). 4‐fluorobutyrylfentanyl (4F‐butyrylfentanyl) critical review report. Expert Committee on Drug Dependence, 39th Meeting. Geneva, Switzerland. https://www.who.int/medicines/access/controlled-substances/4F-Butyrylfentanyl.pdf.
Zhang, X., Zhang, Y., Asgar, J., Niu, K. Y., Lee, J., Lee, K. S., Schneider, M., & Ro, J. Y. (2014). Sex differences in μ‐opioid receptor expression in trigeminal ganglia under a myositis condition in rats. European Journal of Pain, 18(2), 151–161. https://doi.org/10.1002/j.1532-2149.2013.00352.x
Zhao, J., Elgeti, M., O'Brien, E. S., Sár, C. P., Ei Daibani, A., Heng, J., Sun, X., White, E., Che, T., Hubbell, W. L., Kobilka, B. K., & Chen, C. (2024). Ligand efficacy modulates conformational dynamics of the μ‐opioid receptor. Nature, 629(8011), 474–480. https://doi.org/10.1038/s41586-024-07295-2