Department of Pharmacology & Toxicology, Virginia Commonwealth University, 1217 E. Marshall Street, Richmond, VA, 23298-0613, USA.
Department of Pharmacology & Toxicology, Virginia Commonwealth University, 1217 E. Marshall Street, Richmond, VA, 23298-0613, USA.
Neuropharmacology. 2019 May 15;150:210-216. doi: 10.1016/j.neuropharm.2019.02.007. Epub 2019 Feb 5.
Fentanyl and its structurally related compounds have emerged as the most significant contributors to opioid overdose fatalities in recent years. While there is abundant information about the pharmacological effects of fentanyl, far less is known of its more recently abused analogs. The objective of this study was to determine whether fentanyl and several fentanyl-related substances would engender oxycodone-like responding in a mouse model of oxycodone discrimination. Oxycodone was selected as the training drug due to its high selectivity for mu opioid receptors. Compounds that elicited oxycodone-like responding in this procedure would likely evoke overlapping subjective experiences.
Adult male C57BL/6 mice were trained to discriminate 1.3 mg/kg oxycodone from vehicle in a food-reinforced, two-lever choice procedure. Generalization tests were conducted with fentanyl and the following fentanyl-related compounds: ocfentanil, 3-furanyl fentanyl, crotonylfentanyl, and valerylfentanyl.
Fentanyl and each of its analogs completely generalized to the 1.3 mg/kg oxycodone discriminative stimulus and naltrexone pretreatment significantly decreased oxycodone-like responding for each compound. Rank order potency for engendering oxycodone-appropriate responding was ocfentanil > fentanyl > 3-furanyl fentanyl ≈ crotonylfentanyl > oxycodone > valerylfentanyl. Drug doses that evoked full substitution also significantly suppressed response rates compared to vehicle.
These results indicate that the discriminative stimulus, and by extension, the interoceptive and subjective effects of the tested fentanyl analogs, overlap with those of oxycodone. These observations consequentially support the prediction that they would also engender the likelihood for abuse similar to oxycodone. This article is part of the Special Issue entitled 'Opioid Neuropharmacology: Advances in treating pain and opioid addiction'.
近年来，芬太尼及其结构相关化合物已成为阿片类药物过量致死的主要原因。虽然有大量关于芬太尼药理学效应的信息，但对其最近被滥用的类似物知之甚少。本研究的目的是确定芬太尼和几种芬太尼相关物质是否会在小鼠阿片类药物辨别模型中产生类似羟考酮的反应。选择羟考酮作为训练药物是因为它对μ阿片受体具有高度选择性。在该程序中引起类似羟考酮反应的化合物可能会引起重叠的主观体验。
成年雄性 C57BL/6 小鼠在食物强化的双杠杆选择程序中接受 1.3mg/kg 羟考酮和载体的辨别训练。用芬太尼和以下芬太尼相关化合物进行概括测试：ocfentanil、3-呋喃基芬太尼、丙烯酰芬太尼和戊酰芬太尼。
芬太尼和其每种类似物完全概括了 1.3mg/kg 羟考酮的辨别刺激，纳曲酮预处理显著降低了每种化合物的羟考酮样反应。产生羟考酮适当反应的效力顺序为 ocfentanil>芬太尼>3-呋喃基芬太尼≈丙烯酰芬太尼>羟考酮>戊酰芬太尼。与载体相比，诱发完全替代的药物剂量也显著抑制了反应率。
这些结果表明，被测试的芬太尼类似物的辨别刺激，以及由此延伸出的内感受和主观效应，与羟考酮重叠。这些观察结果继而支持了它们也会产生类似于羟考酮的滥用可能性的预测。本文是题为“阿片类神经药理学：治疗疼痛和阿片类药物成瘾的进展”的特刊的一部分。
