Neurod1 modulates opioid antinociceptive tolerance via two distinct mechanisms.
Neurod1 modulates opioid antinociceptive tolerance via two distinct mechanisms.
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Neurod1 通过两种不同的机制调节阿片类镇痛药耐受性。
DOI：
10.1016/j.biopsych.2014.05.013
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发表时间：
2014-11-15
影响因子：
10.6
通讯作者：
Zheng H
中科院分区：
文献类型：
--
作者：
Li W;He S;Zhou Y;Li Y;Hao J;Zhou X;Wang F;Zhang Y;Huang Z;Li Z;Loh HH;Law PY;Zheng H
给予吗啡后，神经源性分化 1 (Neurod1) 的活性降低，导致初级海马神经元树突棘的稳定性、小鼠海马的成体神经发生和药物相关的情境记忆受损。目前的研究检验了 Neurod1 是否会影响阿片类药物耐受的发展。将编码 Neurod1、microRNA-190 (miR-190) 或针对 Neurod1 的短发夹 RNA 的慢病毒单独或组合注射到小鼠海马体中（每次治疗超过 8 只小鼠），以调节 Neurod1 活性。通过甩尾测定测定吗啡和芬太尼的镇痛半有效剂量值，并用于计算耐受性的发展。使用莫里斯水迷宫测定情境学习和记忆。 NeuroD1 活性的降低增加了吗啡和芬太尼的初始抗伤害中位有效剂量值，通过恢复 NeuroD1 活性可以逆转这种情况。相比之下，NeuroD1 活性的降低以时间依赖性方式抑制耐受性的发展，与其对情境记忆的获得和消退的影响平行。此外，由 Nestin 启动子驱动的 miR-190 和 Neurod1 的表达仅调节耐受性的发展，而不调节镇痛中位有效剂量值。 Neurod1 通过情境学习的时间依赖性途径和通过抗伤害的短反应途径调节阿片类药物耐受性的发展。
The activity of neurogenic differentiation 1 (Neurod1) decreases after morphine administration, which leads to impairments of the stability of dendritic spines in primary hippocampal neurons, adult neurogenesis in mouse hippocampi, and drug-associated contextual memory. The current study examined whether Neurod1 could affect the development of opioid tolerance. Lentivirus encoding Neurod1, microRNA-190 (miR-190), or short hairpin RNA against Neurod1 was injected into mouse hippocampi separately or combined (more than eight mice for each treatment) to modulate Neurod1 activity. The antinociceptive median effective dose values of morphine and fentanyl were determined with tail-flick assay and used to calculate development of tolerance. Contextual learning and memory were assayed using the Morris water maze. Decrease in NeuroD1 activity increased the initial antinociceptive median effective dose values of both morphine and fentanyl, which was reversed by restoring NeuroD1 activity. In contrast, decrease in NeuroD1 activity inhibited development of tolerance in a time-dependent manner, paralleling its effects on the acquisition and extinction of contextual memory. In addition, only development of tolerance, but not antinociceptive median effective dose values, was modulated by the expression of miR-190 and Neurod1 driven by Nestin promoter. Neurod1 regulates the developments of opioid tolerance via a time-dependent pathway through contextual learning and a short-response pathway through antinociception.