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.
Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
Pharmacol Biochem Behav. 2021 Sep;208:173242. doi: 10.1016/j.pbb.2021.173242. Epub 2021 Jul 21.
Synthetic opioids have been implicated as the single greatest contributor to rising drug-related fatalities in recent years. This study evaluated mu-opioid receptor (MOR) mediated effects of seven fentanyl-related substances that have emerged in the recreational drug marketplace, and for which there are no existing or only limited in vivo data. Adult male Swiss Webster mice were administered fentanyl-related substances and their effects on nociception and locomotion as compared to MOR agonist standards were observed. In locomotor activity tests, morphine (100, 180 mg/kg), fentanyl (1, 10 mg/kg), beta-methylfentanyl (10 mg/kg), para-methoxyfentanyl (10 mg/kg), fentanyl carbamate (100 mg/kg), and 3-furanylfentanyl (10 mg/kg), elicited significant (p ≤ 0.05) dose-dependent increases in locomotion. However, para-methylfentanyl and beta'-phenylfentanyl did not produce significant effects on locomotion at doses up to 100 mg/kg and phenylfentanyl (100 mg/kg) significantly decreased locomotion. In warm-water tail-withdrawal tests, all substances produced significant dose-dependent increases in antinociception with increasing ED values (95% CI) of fentanyl [0.08 mg/kg (0.04-0.16)] > para-methoxyfentanyl [0.43 mg/kg (0.23-0.77)] > 3-furanylfentanyl [0.51 mg/kg (0.36-0.74)] > beta-methylfentanyl [0.74 mg/kg (0.64-0.85)] > para-methylfentanyl [1.92 mg/kg (1.48-2.45)] > fentanyl carbamate [5.59 mg/kg (4.11-7.54)] > morphine [7.82 mg/kg (5.42-11.0)] > beta'-phenylfentanyl [19.4 mg/kg (11.0-34.4)] > phenylfentanyl [55.2 mg/kg (33.5-93.0)]. Naltrexone (1 mg/kg) increased ED values several fold with decreasing magnitudes of para-methylfentanyl (63.1×) > para-methoxyfentanyl (22.5×) > beta'-phenylfentanyl (21.0×) > 3-furanylfentanyl (20.6×) > beta-methylfentanyl (19.2×) > phenylfentanyl (5.23×) > fentanyl (3.95×) > fentanyl carbamate (2.21×) > morphine (1.48×). These findings expand upon in vivo results from previous studies and establish that the effects of these fentanyl related-related substances are at least in part mediated by the MOR.
合成阿片类药物是近年来导致药物相关死亡人数上升的最大单一因素。本研究评估了在娱乐性药物市场中出现的七种芬太尼相关物质对μ-阿片受体（MOR）的介导作用，这些物质尚无现有或仅有有限的体内数据。成年雄性瑞士 Webster 小鼠给予芬太尼相关物质，并观察其与 MOR 激动剂标准物质相比对痛觉和运动的影响。在运动活性测试中，吗啡（100、180mg/kg）、芬太尼（1、10mg/kg）、β-甲基芬太尼（10mg/kg）、对甲氧基芬太尼（10mg/kg）、芬太尼氨基甲酸酯（100mg/kg）和 3-呋喃芬太尼（10mg/kg）产生了显著的（p≤0.05）剂量依赖性运动增加。然而，在高达 100mg/kg 的剂量下，对甲氧基芬太尼和β'-苯丙芬太尼对运动没有产生显著影响，苯丙芬太尼（100mg/kg）显著降低了运动。在温水尾部撤退测试中，所有物质均产生显著的剂量依赖性镇痛作用，芬太尼的 ED 值（95%CI）增加[0.08mg/kg（0.04-0.16）]>对甲氧基芬太尼[0.43mg/kg（0.23-0.77）]>3-呋喃芬太尼[0.51mg/kg（0.36-0.74）]>β-甲基芬太尼[0.74mg/kg（0.64-0.85）]>对甲氧基芬太尼[1.92mg/kg（1.48-2.45）]>芬太尼氨基甲酸酯[5.59mg/kg（4.11-7.54）]>吗啡[7.82mg/kg（5.42-11.0）]>β'-苯丙芬太尼[19.4mg/kg（11.0-34.4）]>苯丙芬太尼[55.2mg/kg（33.5-93.0）]。纳曲酮（1mg/kg）使对甲氧基芬太尼（63.1×）>对甲氧基芬太尼（22.5×）>β'-苯丙芬太尼（21.0×）>3-呋喃芬太尼（20.6×）>β-甲基芬太尼（19.2×）>苯丙芬太尼（5.23×）>芬太尼（3.95×）>芬太尼氨基甲酸酯（2.21×）>吗啡（1.48×）的 ED 值增加了几倍。这些发现扩展了先前研究中的体内结果，并证实这些芬太尼相关物质的作用至少部分是由 MOR 介导的。
