Neiswanger Carlie, Ruiz Micaela V, Kimball Kandace, Lee Justin D, Land Benjamin, Berndt Andre, Chavkin Charles
Departments of Pharmacology, Seattle, WA.
Bioengineering, University of Washington; Seattle, WA.
bioRxiv. 2024 Dec 17:2024.12.16.628727. doi: 10.1101/2024.12.16.628727.
The endogenous dynorphin/kappa opioid receptor (KOR) system in the brain mediates the dysphoric effects of stress, and KOR antagonists may have therapeutic potential for the treatment of drug addiction, depression, and psychosis. One class of KOR antagonists, the long-acting norBNI-like antagonists, have been suggested to act by causing KOR inactivation through a cJun-kinase mechanism rather than by competitive inhibition. In this study, we screened for other opioid ligands that might produce norBNI-like KOR inactivation and found that nalfurafine (a G-biased KOR agonist) and nalmefene (a KOR partial agonist) also produce long-lasting KOR inactivation. Neither nalfurafine nor nalmefene are completely selective KOR ligands, but KOR inactivation was observed at doses 10-100 fold lower than necessary for mu opioid receptor actions. Daily microdosing with nalfurafine or nalmefene blocked KORs responsible for antinociceptive effects, blocked KORs mediating stress-induced aversion, and mitigated the aversion during acute and protracted withdrawal in fentanyl-dependent mice. Both nalfurafine and nalmefene have long histories of safety and use in humans and could potentially be repurposed for the treatment of dynorphin-mediated stress disorders.
大脑中的内源性强啡肽/κ阿片受体（KOR）系统介导应激的烦躁不安效应，KOR拮抗剂可能对治疗药物成瘾、抑郁症和精神病具有治疗潜力。一类KOR拮抗剂，即长效去甲苄吗啡啉样拮抗剂，被认为是通过cJun激酶机制导致KOR失活而起作用，而非通过竞争性抑制。在本研究中，我们筛选了可能产生去甲苄吗啡啉样KOR失活的其他阿片类配体，发现纳曲酮（一种G偏向性KOR激动剂）和纳美芬（一种KOR部分激动剂）也能产生持久的KOR失活。纳曲酮和纳美芬都不是完全选择性的KOR配体，但在比μ阿片受体作用所需剂量低10至100倍的剂量下观察到了KOR失活。每日微量给予纳曲酮或纳美芬可阻断负责镇痛作用的KOR，阻断介导应激诱导厌恶的KOR，并减轻芬太尼依赖小鼠急性和长期戒断期间的厌恶感。纳曲酮和纳美芬在人类中都有悠久的安全使用历史，有可能被重新用于治疗强啡肽介导的应激障碍。
