Respiratory depressant effects of fentanyl analogs are opioid receptor-mediated.

Autor: Varshneya NB; Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA. Electronic address: nvarshn2@jhmi.edu., Hassanien SH; Forensic Chemistry Division, Cayman Chemical Company, Ann Arbor, MI, USA., Holt MC; Forensic Chemistry Division, Cayman Chemical Company, Ann Arbor, MI, USA., Stevens DL; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA., Layle NK; Forensic Chemistry Division, Cayman Chemical Company, Ann Arbor, MI, USA., Bassman JR; Forensic Chemistry Division, Cayman Chemical Company, Ann Arbor, MI, USA., Iula DM; Forensic Chemistry Division, Cayman Chemical Company, Ann Arbor, MI, USA., Beardsley PM; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Center for Biomarker Research & Precision Medicine, Virginia Commonwealth University School of Pharmacy, Richmond, VA, USA.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2022 Jan; Vol. 195, pp. 114805. Date of Electronic Publication: 2021 Oct 19.
DOI: 10.1016/j.bcp.2021.114805
Abstrakt: Opioid-related fatalities involving synthetic opioids have reached unprecedented levels. This study evaluated the respiratory depressant effects of seven fentanyl analogs that have either emerged in the illicit drug supply or been identified in toxicological analyses following fatal or non-fatal intoxications. Adult male Swiss Webster mice were administered fentanyl analogs (isobutyrylfentanyl, crotonylfentanyl, para-methoxyfentanyl, para-methoxybutyrylfentanyl, 3-furanylfentanyl, thiophenefentanyl, and benzodioxolefentanyl) and their effects on minute volume as compared to mu-opioid receptor (MOR) agonist standards (fentanyl, morphine, and buprenorphine) were measured using whole body plethysmography (WBP). All drugs elicited significant (p ≤ 0.05) hypoventilation relative to vehicle for at least one dose tested: morphine (1, 3.2, 10, 32 mg/kg), buprenorphine, (0.032, 0.1, 0.32, 1, 3.2 mg/kg), fentanyl (0.0032, 0.01, 0.032, 0.1, 1, 32 mg/kg), isobutyrylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), crotonylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), para-methoxyfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), para-methoxybutyrylfentanyl (0.32, 1, 3.2, 10 mg/kg), 3-furanylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), thiophenefentanyl (1, 3.2, 10, 32, 100 mg/kg), and benzodioxolefentanyl (3.2, 10, 32, 100 mg/kg). The ED 50 values for hypoventilation showed a rank order of potency as follows: fentanyl (ED 50  = 0.96 mg/kg) > 3-furanylfentanyl (ED 50  = 2.60 mg/kg) > crotonylfentanyl (ED 50  = 2.72 mg/kg) > para-methoxyfentanyl (ED 50  = 3.31 mg/kg) > buprenorphine (ED 50  = 10.8 mg/kg) > isobutyrylfentanyl (ED 50  = 13.5 mg/kg) > para-methoxybutyrylfentanyl (ED 50  = 16.1 mg/kg) > thiophenefentanyl (ED 50  = 18.0 mg/kg) > morphine (ED 50  = 55.3 mg/kg) > benzodioxolefentanyl (ED 50  = 10,168 mg/kg). A naloxone pretreatment (10 mg/kg) attenuated the hypoventilatory effects of all drugs. These results establish that the respiratory depressant effects of these fentanyl analogs are at least in part mediated by the MOR.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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