Discriminative stimulus effects of carfentanil in rats discriminating fentanyl: Differential antagonism by naltrexone
Discriminative stimulus effects of carfentanil in rats discriminating fentanyl: Differential antagonism by naltrexone
复制标题
卡芬太尼对大鼠辨别芬太尼的辨别刺激效应： 纳曲酮的差异拮抗作用
DOI：
10.1016/j.drugalcdep.2021.108599
复制
发表时间：
2021-02-22
影响因子：
4.2
通讯作者：
France, Charles P.
中科院分区：
文献类型：
--
作者：
Flynn, Shawn M.;France, Charles P.
背景：由阿片类药物引起的大量死亡涉及芬太尼和/或其一种非常有效的类似物（例如卡芬太尼）。一些临床报告表明，与其他阿片受体激动剂相比，可能需要更大剂量的阿片受体拮抗剂来逆转卡芬太尼的作用，尽管这尚未在体内进行广泛的检查。目前的研究比较了芬太尼、卡芬太尼和海洛因的辨别刺激作用，以及纳曲酮对它们的拮抗作用。 方法：训练 8 只雄性 Sprague-Dawley 大鼠区分 10.0 µg/kg 芬太尼和盐水，同时在固定比例 10 的食物呈现方案下做出反应。确定阿片受体激动剂芬太尼 (1.0?32.0 µg/kg)、卡芬太尼 (0.1?3.2 µg/kg) 和海洛因 (10.0?320.0 µg/kg) 的剂量效应曲线，然后用 0.1 mg/kg 纳曲酮预处理 15 分钟后重新确定。 结果：芬太尼、卡芬太尼和海洛因海洛因剂量依赖性地增加了芬太尼相关杠杆的反应并降低了杠杆按压的速率。卡芬太尼和海洛因在芬太尼相关杠杆上引发 >80% 的反应时，分别比芬太尼强约 10 倍和弱约 10 倍。用0.1 mg/kg纳曲酮预处理导致芬太尼和海洛因剂量效应曲线显着右移，但卡芬太尼剂量效应曲线没有明显右移。结论：与芬太尼和海洛因相比，纳曲酮减弱卡芬太尼歧视性刺激效应的有效性存在差异，这表明卡芬太尼与其他阿片类药物相比，如何发挥其歧视性刺激效应可能存在差异。需要进一步评估卡芬太尼和其他阿片类药物之间潜在的药理学和行为差异，特别是在毒性方面。
Background: A significant number of deaths caused by opioids involve fentanyl and/or one of its very potent analogs (e.g., carfentanil). Some clinical reports suggest larger doses of opioid receptor antagonists may be required to reverse the effects of carfentanil compared with other opioid receptor agonists, although this has not been examined extensively in vivo. The current study compared the discriminative stimulus effects of fentanyl, carfentanil, and heroin, and their antagonism by naltrexone.Methods: Eight male Sprague-Dawley rats were trained to discriminate 10.0 ?g/kg fentanyl from saline while responding under a fixed-ratio 10 schedule of food presentation. Dose-effect curves were determined for the opioid receptor agonists fentanyl (1.0?32.0 ?g/kg), carfentanil (0.1?3.2 ?g/kg), and heroin (10.0?320.0 ?g/kg), then redetermined following a 15-minute pretreatment with 0.1 mg/kg naltrexone.Results: Fentanyl, carfentanil, and heroin dose-dependently increased responding on the fentanyl-associated lever and decreased the rate of lever pressing. Carfentanil and heroin were approximately 10-fold more and less potent, respectively, than fentanyl at eliciting >80 % responding on the fentanyl-associated lever. Pretreatment with 0.1 mg/kg naltrexone resulted in a significant rightward shift in the fentanyl and heroin but not carfentanil dose-effect curves.Conclusions: Differences in the effectiveness of naltrexone to attenuate the discriminative stimulus effects of carfentanil, compared with fentanyl and heroin, suggest that there may be differences in how carfentanil exerts its discriminative stimulus effects compared with other opioids. Further evaluation is needed of potential pharmacological and behavioral differences between carfentanil and other opioids, particularly in the context of toxicity.