Department of Anesthesiology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China.
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Acta Pharmacol Sin. 2022 Mar;43(3):577-587. doi: 10.1038/s41401-021-00677-6. Epub 2021 May 25.
Major depression disorder is a severe and recurrent neuropsychological disorder characterized by lowered mood and social activity and cognitive impairment. Owing to unclear molecular mechanisms of depression, limited interventions are available in clinic. In this study we investigated the role of dynorphin/κ opioid receptor system in the development of depression. Mice were subjected to chronic social defeat stress for 14 days. Chronic social defeat stress induced significant social avoidance in mice characterized by decreased time duration in the interaction zone and increased time duration in the corner zone. Pre-administration of a κ opioid receptor antagonist norBNI (10 mg/kg, i.p.) could prevent the development of social avoidance induced by chronic social defeat stress. Social avoidance was not observed in κ opioid receptor knockout mice subjected to chronic social defeat stress. We further revealed that social defeat stress activated c-fos and ERK signaling in the amygdala without affecting the NAc, hippocampus and hypothalamus, and ERK activation was blocked by systemic injection of norBNI. Finally, the expression of dynorphin A, the endogenous ligand of κ opioid receptor, was significantly increased in the amygdala following social defeat stress; microinjection of norBNI into the amygdala prevented the development of depressive-like behaviors caused by social defeat stress. The present study demonstrates that upregulated dynorphin/κ opioid receptor system in the amygdala leads to the emergence of depression following chronic social defeat stress, and sheds light on κ opioid receptor antagonists as potential therapeutic agents for the prevention and treatment of depression following chronic stress.
重度抑郁症是一种严重且反复发作的神经心理障碍，其特征为情绪低落、社会活动减少和认知障碍。由于对抑郁症的分子机制尚不清楚，目前临床上的干预措施有限。在这项研究中，我们研究了强啡肽/κ 阿片受体系统在抑郁症发展中的作用。小鼠接受慢性社会挫败应激 14 天。慢性社会挫败应激诱导小鼠出现显著的社会回避，表现为在互动区的时间减少和在角落区的时间增加。κ 阿片受体拮抗剂 norBNI（10mg/kg，腹腔注射）预先给药可预防慢性社会挫败应激引起的社会回避。慢性社会挫败应激的 κ 阿片受体敲除小鼠没有观察到社会回避。我们进一步揭示，社会挫败应激激活了杏仁核中的 c-fos 和 ERK 信号，但不影响 NAc、海马体和下丘脑，而 norBNI 的全身注射则阻断了 ERK 激活。最后，社交挫败应激后，强啡肽 A（κ 阿片受体的内源性配体）在杏仁核中的表达显著增加；norBNI 微注射到杏仁核中可预防社交挫败应激引起的抑郁样行为的发展。本研究表明，杏仁核中上调的强啡肽/κ 阿片受体系统导致慢性社会挫败应激后出现抑郁，提示 κ 阿片受体拮抗剂可能成为慢性应激后预防和治疗抑郁症的潜在治疗药物。
