Department of Anesthesiology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
Atelerix Life Sciences Inc., 300 East Main Street, Suite 202, Charlottesville, VA, USA.
Sci Rep. 2024 Apr 20;14(1):9091. doi: 10.1038/s41598-024-59551-0.
N-acetyl-L-cysteine (L-NAC) is a proposed therapeutic for opioid use disorder. This study determined whether co-injections of L-NAC (500 μmol/kg, IV) or its highly cell-penetrant analogue, L-NAC methyl ester (L-NACme, 500 μmol/kg, IV), prevent acquisition of acute physical dependence induced by twice-daily injections of fentanyl (125 μg/kg, IV), and overcome acquired dependence to these injections in freely-moving male Sprague Dawley rats. The injection of the opioid receptor antagonist, naloxone HCl (NLX; 1.5 mg/kg, IV), elicited a series of withdrawal phenomena (i.e. behavioral and cardiorespiratory responses, hypothermia and body weight loss) in rats that received 5 or 10 injections of fentanyl and similar numbers of vehicle co-injections. With respect to the development of dependence, the NLX-precipitated withdrawal phenomena were reduced in rats that received had co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme. In regard to overcoming established dependence, the NLX-precipitated withdrawal phenomena in rats that had received 10 injections of fentanyl (125 μg/kg, IV) were reduced in rats that had received co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme beginning with injection 6 of fentanyl. This study provides compelling evidence that co-injections of L-NAC and L-NACme prevent the acquisition of physical dependence and overcome acquired dependence to fentanyl in male rats. The higher efficacy of L-NACme is likely due to its greater cell penetrability in brain regions mediating dependence to fentanyl and interaction with intracellular signaling cascades, including redox-dependent processes, responsible for the acquisition of physical dependence to fentanyl.
N-乙酰-L-半胱氨酸（L-NAC）是一种治疗阿片类药物使用障碍的药物。本研究旨在确定 L-NAC（500μmol/kg，静脉注射）或其具有高细胞穿透性的类似物 L-NAC 甲酯（L-NACme，500μmol/kg，静脉注射）是否可以预防每日两次注射芬太尼（125μg/kg，静脉注射）引起的急性身体依赖的发生，并克服自由活动的雄性 Sprague Dawley 大鼠对这些注射的获得性依赖。阿片受体拮抗剂盐酸纳洛酮（NLX；1.5mg/kg，静脉注射）在接受 5 或 10 次芬太尼注射和相同数量的载体共注射的大鼠中引起一系列戒断现象（即行为和心肺反应、体温过低和体重减轻）。就依赖性的发展而言，接受 L-NAC 共注射的大鼠中 NLX 诱发的戒断现象减少，而接受 L-NACme 共注射的大鼠中减少更多。关于克服已建立的依赖，接受 10 次芬太尼（125μg/kg，静脉注射）注射的大鼠中 NLX 诱发的戒断现象在接受 L-NAC 共注射的大鼠中减少，而在接受 L-NACme 共注射的大鼠中减少更多，从芬太尼第 6 次注射开始。这项研究提供了令人信服的证据，表明 L-NAC 和 L-NACme 的共注射可预防身体依赖的发生，并克服雄性大鼠对芬太尼的获得性依赖。L-NACme 的更高疗效可能归因于其在介导对芬太尼的依赖的大脑区域中更高的细胞穿透性，以及与细胞内信号级联的相互作用，包括依赖于氧化还原的过程，这些过程负责对芬太尼的身体依赖的发生。
