CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences of Guangzhou Medical University, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China.
FASEB J. 2020 Apr;34(4):5917-5930. doi: 10.1096/fj.201902873R. Epub 2020 Mar 10.
The abilities of opioids to activate downstream signaling pathways normally depend on the binding between opioids and their receptors. However, opioids may also function in a receptor-independent manner, especially in neural stem cells (NSCs) in which the expression of opioid receptors and endogenous opioid agonists is low. When two opioids, morphine and naloxone, were used during the early stage of NSC differentiation, increased neurogenesis was observed. However, naloxone methiodide, a membrane impenetrable analog of naloxone, did not affect the NSC differentiation. The abilities of morphine and naloxone to facilitate neurogenesis were also observed in opioid receptor-knockout NSCs. Therefore, morphine and naloxone promote neurogenesis in a receptor-independent manner at least during the early stage. In addition, the receptor-independent functions of opioids were not observed in methylcytosine dioxygenase ten-eleven translocation 1 (Tet1) knockout NSCs. When the expression of opioid receptors increased and the expression of Tet1 decreased during the late stage of NSC differentiation, morphine, but not naloxone, inhibited neurogenesis via traditional receptor-dependent and miR181a-Prox1-Notch-related pathway. In summary, the current results demonstrated the time-dependent effects of opioids during the differentiation of NSCs and provided additional insight on the complex functions of opioids.
阿片类药物激活下游信号通路的能力通常取决于阿片类药物与其受体之间的结合。然而，阿片类药物也可能以受体非依赖的方式发挥作用，特别是在神经干细胞（NSC）中，阿片类受体和内源性阿片类激动剂的表达水平较低。当两种阿片类药物吗啡和纳洛酮在 NSC 分化的早期阶段使用时，观察到神经发生增加。然而，纳洛酮甲碘化物（naloxone methiodide），一种纳洛酮不可穿透的膜类似物，并不影响 NSC 分化。在阿片受体敲除 NSC 中也观察到吗啡和纳洛酮促进神经发生的能力。因此，吗啡和纳洛酮至少在早期以受体非依赖的方式促进神经发生。此外，在甲基胞嘧啶双加氧酶 ten-eleven 易位 1（Tet1）敲除 NSC 中未观察到阿片类药物的受体非依赖性功能。当 NSC 分化晚期阿片受体表达增加且 Tet1 表达减少时，吗啡而非纳洛酮通过传统的受体依赖性和 miR181a-Prox1-Notch 相关途径抑制神经发生。总之，目前的结果表明阿片类药物在 NSC 分化过程中存在时间依赖性效应，并为阿片类药物的复杂功能提供了更多的见解。
