Neiswanger Carlie, Ruiz Micaela V, Kimball Kandace, Lee Justin Daho, Land Benjamin B, Berndt Andre, Chavkin Charles
Department of Pharmacology, University of Washington, Seattle, Washington.
Department of Bioengineering, University of Washington, Seattle, Washington.
Biol Psychiatry. 2025 Apr 4. doi: 10.1016/j.biopsych.2025.03.021.
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 norbinaltorphimine (norBNI)-like antagonists, have been suggested to act by causing KOR inactivation through a c-Jun-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 produced long-lasting KOR inactivation.
Neither nalfurafine nor nalmefene is a completely selective KOR ligand, but KOR inactivation was observed at doses 10- to 100-fold lower than necessary for mu opioid receptor actions. KOR inactivation is sex dependent, and we show that nalfurafine causes peroxide production only during estrus (low-estrogen state) or after progesterone treatment of female mice. Because KOR inactivation recovers slowly, daily treatment with submaximal drug doses causes accumulating inhibition. Daily microdosing with nalfurafine or nalmefene blocked KORs responsible for antinociceptive effects, blocked KORs mediating stress-induced aversion, mitigated KOR-mediated dysphoria during acute and protracted withdrawal in opioid-dependent mice, and blocked KOR-induced prolactin secretion. In contrast, KORs mediating the diuretic and antipruritic effects were not regulated by JNK (c-Jun N-terminal kinase).
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拮抗剂可能具有治疗药物成瘾、抑郁症和精神病的潜力。一类KOR拮抗剂，即长效去甲丁丙诺啡（norBNI）样拮抗剂，被认为是通过c-Jun激酶机制导致KOR失活而起作用，而非竞争性抑制。
在本研究中，我们筛选了其他可能产生类似norBNI的KOR失活的阿片样物质配体，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。KOR失活具有性别依赖性，我们发现纳曲酮仅在发情期（低雌激素状态）或对雌性小鼠进行孕酮处理后才会导致过氧化物产生。由于KOR失活恢复缓慢，用次最大剂量药物每日治疗会导致抑制作用累积。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，减轻阿片类药物依赖小鼠急性和长期戒断期间KOR介导的烦躁不安，并阻断KOR诱导的催乳素分泌。相比之下，介导利尿和止痒作用的KOR不受JNK（c-Jun氨基末端激酶）调节。
纳曲酮和纳美芬在人类中都有长期的安全使用历史，有可能被重新用于治疗强啡肽介导的应激障碍。
