Bedard Madigan L, Huang Xi-Ping, Murray Jackson G, Nowlan Alexandra C, Conley Sara Y, Mott Sarah E, Loyack Samuel J, Cline Calista A, Clodfelter Caroline G, Dasgupta Nabarun, Krumm Brian, Roth Bryan L, McElligott Zoe A
Department of Pharmacology, The University of North Carolina at Chapel Hill; Chapel Hill, 27599, USA.
Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill; Chapel Hill, 27599, USA.
Addict Neurosci. 2024 Jun;11. doi: 10.1016/j.addicn.2024.100155. Epub 2024 May 3.
Xylazine is in the unregulated drug supply at increasing rates, usually combined with fentanyl, necessitating understanding of its pharmacology. Despite commentary from politicians, and public health officials, it is unknown how xylazine impacts naloxone efficacy, and. few studies have examined it alone. Here, we examine the impact of xylazine alone and in combination with fentanyl on several behaviors in mice. Surprisingly, naloxone precipitates withdrawal from xylazine and fentanyl/xylazine coadministration, with enhanced sensitivity in females. Further, xylazine is a full agonist at kappa opioid receptors, a potential mechanism for its naloxone sensitivity. Finally, we demonstrate surprising effects of xylazine to kappa opioid antagonism, which are relevant for public health considerations. These data address an ongoing health crisis and will help inform critical policy and healthcare decisions.
赛拉嗪在不受管制的药物供应中的比例不断增加，通常与芬太尼混合使用，因此有必要了解其药理学特性。尽管政界人士和公共卫生官员发表了评论，但赛拉嗪如何影响纳洛酮的疗效尚不清楚，而且单独研究它的研究很少。在这里，我们研究了赛拉嗪单独使用以及与芬太尼联合使用对小鼠几种行为的影响。令人惊讶的是，纳洛酮会引发赛拉嗪和芬太尼/赛拉嗪联合用药后的戒断反应，雌性小鼠的敏感性增强。此外，赛拉嗪是κ阿片受体的完全激动剂，这是其对纳洛酮敏感的潜在机制。最后，我们证明了赛拉嗪对κ阿片拮抗作用有惊人的效果，这与公共卫生考虑相关。这些数据解决了当前的健康危机，并将有助于为关键政策和医疗决策提供信息。
