Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Alkermes, Inc., Biology, Waltham, MA, United States of America.
Eur Neuropsychopharmacol. 2023 Jul;72:9-17. doi: 10.1016/j.euroneuro.2023.03.010. Epub 2023 Apr 9.
Depression is a widespread disorder with a significant burden on individuals and society. There are various available treatments for patients with depression. However, not all patients respond adequately to their treatment. Recently, the opioid system has regained interest in depression studies. Research in animals and humans suggest that blocking the kappa opioid receptor (KOR) may potentially alleviate the symptoms of depression. The mechanism behind this effect is not fully understood. Stress and alterations in hypothalamic-pituitary-adrenal axis (HPA-axis) activity are thought to play a crucial role in depression. This study aimed to characterize stress hormones and stress-related protein expression following activation of KOR using a selective agonist. The longitudinal effect was investigated 24 h after KOR activation using the selective agonist U50,488 in Sprague Dawley rats. Stress-related hormones and protein expression patterns were explored using multiplex bead-based assays and western blotting. We found that KOR activation caused an increase in both adrenocorticotropic hormone (ACTH) and corticosterone (CORT) in serum. Regarding protein assays in different brain regions, phosphorylated glucocorticoid receptors also increased significantly in thalamus (THL), hypothalamus (HTH), and striatum (STR). C-Fos increased time-dependently in THL following KOR activation, extracellular signal-regulated kinases 1/2 (ERK1/2) increased significantly in STR and amygdala (AMG), while phosphorylated ERK1/2 decreased during the first 2 h and then increased again in AMG and prefrontal cortex (PFC). This study shows that KOR activation alters the HPA axis and ERK signaling which may cause to develop mood disorders.
抑郁症是一种广泛存在的疾病，给个人和社会带来了巨大的负担。目前有各种针对抑郁症患者的治疗方法。然而，并非所有患者对其治疗都有足够的反应。最近，阿片样物质系统在抑郁症研究中重新引起了人们的兴趣。动物和人类的研究表明，阻断κ阿片受体（KOR）可能潜在地缓解抑郁症的症状。这种作用的机制尚未完全理解。压力和下丘脑-垂体-肾上腺轴（HPA 轴）活动的改变被认为在抑郁症中起着至关重要的作用。本研究旨在使用选择性激动剂来描述 KOR 激活后应激激素和与应激相关的蛋白表达。使用选择性激动剂 U50,488 在 Sprague Dawley 大鼠中，在 KOR 激活后 24 小时内研究了纵向效应。使用基于多重珠子的测定法和 Western 印迹法研究了与应激相关的激素和蛋白表达模式。我们发现，KOR 激活会导致血清中促肾上腺皮质激素（ACTH）和皮质酮（CORT）的增加。关于不同脑区的蛋白测定，丘脑（THL）、下丘脑（HTH）和纹状体（STR）中的磷酸化糖皮质激素受体也显著增加。KOR 激活后，THL 中的 C-Fos 呈时间依赖性增加，STR 和杏仁核（AMG）中的细胞外信号调节激酶 1/2（ERK1/2）显著增加，而 AMG 和前额叶皮质（PFC）中的磷酸化 ERK1/2 在最初的 2 小时内减少，然后再次增加。这项研究表明，KOR 激活改变了 HPA 轴和 ERK 信号通路，这可能导致情绪障碍的发生。
