Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China; Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Eur J Pharmacol. 2023 Mar 5;942:175532. doi: 10.1016/j.ejphar.2023.175532. Epub 2023 Jan 26.
Depressive disorder is a psychiatric disease characterized by its main symptoms of low mood and anhedonia. Due to its complex etiology, current clinical treatments for depressive disorder are limited. In this study, we assessed the role of the δ opioid receptor (δOR) system in the development of chronic-restraint-stressed (CRS)-induced depressive behaviors. We employed a 21-day CRS model and detected the c-fos activation and protein levels' changes in enkephalin (ENK)/δOR. It was found that the hippocampus and amygdala were involved in CRS-induced depression. The expression of pro-enkephalin (PENK), the precursors of the endogenous ligand for δOR, was significantly decreased in the hippocampus and amygdala following CRS. We then treated the mice with SNC80, a specific δOR agonist, to examine its anti-depressant effects in the tail suspension test (TST), forced swimming test (FST), and sucrose preference test (SPT). SNC80 administration significantly reversed depressive-like behaviors, and this antidepressant effect could be blocked by a TrkB inhibitor: ANA-12. Although ANA-12 treatment had no significant effect on the expression of ENK/δOR, it blocked the promoting effects of brain-derived neurotrophic factor (BDNF)/tyrosine kinase B(TrkB) signaling by SNC80 in the hippocampus and amygdala. Therefore, the present study demonstrates that SNC80 exerts anti-depressant effects by up-regulating the BDNF/TrkB signaling pathway in the hippocampus and amygdala in CRS-induced depression and provides evidence that δOR's agonists may be potential anti-depressant therapeutic agents.
抑郁障碍是一种以情绪低落和快感缺失为主要特征的精神疾病。由于其复杂的病因，目前临床治疗抑郁障碍的方法有限。在本研究中，我们评估了 δ 阿片受体（δOR）系统在慢性束缚应激（CRS）诱导的抑郁行为发展中的作用。我们采用了 21 天 CRS 模型，并检测了脑啡肽（ENK）/δOR 中的 c-fos 激活和蛋白水平变化。结果发现，海马体和杏仁核参与了 CRS 诱导的抑郁。CRS 后，海马体和杏仁核中 δOR 内源性配体前体前啡肽（PENK）的表达明显减少。然后，我们用 SNC80（一种特异性 δOR 激动剂）治疗小鼠，在悬尾试验（TST）、强迫游泳试验（FST）和蔗糖偏好试验（SPT）中观察其抗抑郁作用。SNC80 给药显著逆转了抑郁样行为，而这种抗抑郁作用可被 TrkB 抑制剂 ANA-12 阻断。尽管 ANA-12 处理对 ENK/δOR 的表达没有显著影响，但它阻断了 SNC80 在海马体和杏仁核中对脑源性神经营养因子（BDNF）/酪氨酸激酶 B（TrkB）信号的促进作用。因此，本研究表明，SNC80 通过上调 CRS 诱导的抑郁中海马体和杏仁核中的 BDNF/TrkB 信号通路发挥抗抑郁作用，并为 δOR 激动剂可能成为潜在的抗抑郁治疗药物提供了证据。
