Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou, People's Republic of China.
Department of Pharmacy, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China.
Stem Cells. 2021 May;39(5):600-616. doi: 10.1002/stem.3334. Epub 2021 Jan 15.
Although the roles of opioid receptors in neurogenesis have been implicated in previous studies, the mechanism by which κ-opioid receptor (OPRK1) regulates adult neurogenesis remains elusive. We now demonstrate that two agonists of OPRK1, U50,488H and dynorphin A, inhibit adult neurogenesis by hindering neuronal differentiation of mouse hippocampal neural stem cells (NSCs), both in vitro and in vivo. This effect was blocked by nor-binaltorphimine (nor-BNI), a specific antagonist of OPRK1. By examining neurogenesis-related genes, we found that OPRK1 agonists were able to downregulate the expression of Pax6, Neurog2, and NeuroD1 in mouse hippocampal NSCs, in a way that Pax6 regulates the transcription of Neurog2 and Neurod1 by directly interacting with their promoters. Moreover, this effect of OPRK1 was accomplished by inducing expression of miR-7a, a miRNA that specifically targeted Pax6 by direct interaction with its 3'-UTR sequence, and thereby decreased the levels of Pax6, Neurog2, and NeuroD1, thus resulted in hindrance of neuronal differentiation of NSCs. Thus, by modulating Pax6/Neurog2/NeuroD1 activities via upregulation of miR-7a expression, OPRK1 agonists hinder the neuronal differentiation of NSCs and hence inhibit adult neurogenesis in mouse hippocampus.
虽然阿片受体在神经发生中的作用在以前的研究中已经被涉及，但κ-阿片受体（OPRK1）调节成年神经发生的机制仍然难以捉摸。我们现在证明，OPRK1 的两种激动剂，U50,488H 和强啡肽 A，通过阻碍小鼠海马神经干细胞（NSCs）的神经元分化，无论是在体外还是体内，都抑制成年神经发生。这种作用被 nor-binaltorphimine（nor-BNI）阻断，nor-BNI 是 OPRK1 的一种特异性拮抗剂。通过检查神经发生相关基因，我们发现 OPRK1 激动剂能够下调小鼠海马 NSCs 中 Pax6、Neurog2 和 NeuroD1 的表达，这种方式是 Pax6 通过直接与其启动子相互作用来调节 Neurog2 和 Neurod1 的转录。此外，OPRK1 通过诱导 miR-7a 的表达来实现这种作用，miR-7a 通过与 Pax6 的 3'-UTR 序列直接相互作用特异性靶向 Pax6，从而降低 Pax6、Neurog2 和 NeuroD1 的水平，从而阻碍 NSCs 的神经元分化。因此，通过上调 miR-7a 的表达来调节 Pax6/Neurog2/NeuroD1 的活性，OPRK1 激动剂阻碍 NSCs 的神经元分化，从而抑制小鼠海马体中的成年神经发生。
