Dynorphin activation of kappa opioid receptor reduces neuronal excitability in the paraventricular nucleus of mouse thalamus
Dynorphin activation of kappa opioid receptor reduces neuronal excitability in the paraventricular nucleus of mouse thalamus
复制标题
强啡肽激活卡帕阿片受体降低小鼠丘脑室旁核神经元兴奋性
DOI：
10.1016/j.neuropharm.2015.05.030
复制
发表时间：
2015-10-01
影响因子：
4.7
通讯作者：
Liu, Yong
中科院分区：
文献类型：
--
作者：
Chen, Zhiheng;Tang, Yamei;Liu, Yong
据报道，κ阿片受体（KOR）表达于丘脑室旁核（PVT），这是一个与唤醒、药物奖励和应激相关的脑区。虽然发现PVT内输注KOR激动剂抑制药物寻求行为，但内源性KOR激动剂是否直接调节PVT神经元活性仍不清楚。在这里，我们研究了内源性KOR激动剂强啡肽-A（Dyn-A）对不同发育年龄小鼠PVT神经元兴奋性的影响。我们发现Dyn-A通过直接的突触后超极化强烈抑制PVT神经元。在电压钳条件下，Dyn-A在前PVT（aPVT）的大多数神经元中诱发明显的外向电流，而在后PVT（pPVT）的少数神经元中诱发明显的外向电流。Dyn-A电流被KOR拮抗剂nor-BNI、Ba ~（2+）和不可水解GDP类似物GDP-β-s阻断，表明Dyn-A激活KOR并开放PVT神经元G蛋白偶联内向整流钾通道。更有趣的是，通过比较不同年龄小鼠aPVT神经元的Dyn-A电流，我们发现Dyn-A在青春期前和青春期早期的小鼠aPVT神经元中诱发显著更大的电流。另外，Dyn-A激活KOR不引起PVT神经元明显的脱敏，而激活μ阿片受体（莫尔）则引起PVT神经元μ受体本身的明显脱敏，同时也引起KOR的异源性脱敏。总之，我们的研究结果表明，Dyn-A激活KOR并抑制不同年龄尤其是青春期周围小鼠的aPVT神经元，这表明KOR在调节aPVT相关脑功能中可能发挥作用，包括青春期的应激反应和药物寻求行为。(C)2015爱思唯尔有限公司版权所有。
It has been reported that kappa opioid receptor (KOR) is expressed in the paraventricular nucleus of thalamus (PVT), a brain region associated with arousal, drug reward and stress. Although intra-PVT infusion of KOR agonist was found to inhibit drug-seeking behavior, it is still unclear whether endogenous KOR agonists directly regulate PVT neuron activity. Here, we investigated the effect of the endogenous KOR agonist dynorphin-A (Dyn-A) on the excitability of mouse PVT neurons at different developmental ages. We found Dyn-A strongly inhibited PVT neurons through a direct postsynaptic hyperpolarization. Under voltage-clamp configuration, Dyn-A evoked an obvious outward current in majority of neurons tested in anterior PVT (aPVT) but only in minority of neurons in posterior PVT (pPVT). The Dyn-A current was abolished by KOR antagonist nor-BNI, Ba2+ and non-hydrolyzable GDP analogue GDP-beta-s, indicating that Dyn-A activates KOR and opens G-protein-coupled inwardly rectifying potassium channels in PVT neurons. More interestingly, by comparing Dyn-A currents in aPVT neurons of mice at various ages, we found Dyn-A evoked significant larger current in aPVT neurons from mice around prepuberty and early puberty stage. In addition, KOR activation by Dyn-A didn't produce obvious desensitization, while mu opioid receptor (MOR) activation induced obvious desensitization of mu receptor itself and also heterologous desensitization of KOR in PVT neurons. Together, our findings indicate that Dyn-A activates KOR and inhibits aPVT neurons in mice at various ages especially around puberty, suggesting a possible role of KOR in regulating aPVT-related brain function including stress response and drug-seeking behavior during adolescence. (C) 2015 Elsevier Ltd. All rights reserved.