Rewarding Morphine-Induced Synaptic Function of δ-Opioid Receptors on Central Glutamate Synapses
Rewarding Morphine-Induced Synaptic Function of δ-Opioid Receptors on Central Glutamate Synapses
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DOI：
10.1124/jpet.108.148908
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发表时间：
2009-04-01
影响因子：
3.5
通讯作者：
Pan, Zhizhong Z.
中科院分区：
文献类型：
--
作者：
Bie, Bihua;Zhu, Wei;Pan, Zhizhong Z.
阿片类药物的奖赏效应是阿片类药物滥用和成瘾强迫行为的驱动力，主要由 mu-阿片受体介导。然而，δ-阿片受体（DOR）在阿片类药物奖赏和成瘾中的作用仍然知之甚少。最近发现的慢性阿片类药物暴露后感觉神经元胞吐易位的适应性 DOR 特性为探索这种精神神经疾病中的 DOR 功能提供了新的概念思路。在这项研究中，我们研究了杏仁核中央核 (CeA) 神经元中 DOR 的潜在适应性功能，杏仁核是一种前脑结构，在介导药物成瘾中的刺激奖励学习方面日益受到认可。利用 CeA 切片的全细胞记录，我们发现，在表现出吗啡诱导的条件性位置偏好行为（药物奖励的行为测量）的大鼠中，CeA 神经元中谷氨酸突触的整体突触强度显着增强。选择性 DOR 激动剂 [D-Pen(2)、D-Pen(5)]-脑啡肽对对照大鼠神经元的谷氨酸兴奋性突触后电流 (EPSC) 无明显影响，但对吗啡治疗大鼠神经元的突触电流产生显着的剂量依赖性抑制。 EPSC 特性的详细分析表明，DOR 激活通过减少突触前谷氨酸的释放来抑制 EPSC，表明功能性 DOR 出现在突触前谷氨酸末端。吗啡治疗还显着增加了突触体 CeA 制剂中的 DOR 蛋白。这些发现为突触前 DOR 对吗啡改变的关键突触活动的适应性调节提供了功能证据，因此暗示 DOR 可能在阿片类药物奖赏和成瘾中发挥重要作用。
The rewarding effect of opioids, the driving force for compulsive behaviors of opioid abuse and addiction, is primarily mediated by the mu-opioid receptor. However, the role of the delta-opioid receptor (DOR) in opioid reward and addiction is still poorly understood. The recently discovered adaptive DOR property of exocytotic translocation in sensory neurons after chronic opioid exposure provides a new avenue of conceptual thoughts to exploring the DOR function in this psychoneurological disease. In this study, we investigated potential adaptive function of DOR in neurons of the central nucleus of the amygdala (CeA), a forebrain structure increasingly recognized for mediating stimulus reward learning in drug addiction. Using whole-cell recordings in CeA slices, we found that in rats displaying morphine-induced behavior of conditioned place preference, a behavioral measure of drug reward, the overall synaptic strength of glutamate synapses in CeA neurons was significantly enhanced. The selective DOR agonist [D-Pen(2), D-Pen(5)]-enkephalin, having no apparent effect on glutamatergic excitatory postsynaptic current (EPSC) in neurons from control rats, produced a significant, dose-dependent inhibition of the synaptic current in neurons from those morphine-treated rats. Detailed analyses of EPSC properties revealed that DOR activation inhibited the EPSC by reducing presynaptic release of glutamate, indicating functional DOR emerging on presynaptic glutamate terminals. The morphine treatment also significantly increased DOR proteins in CeA preparations of synaptosomes. These findings provide functional evidence for an adaptive modulation by presynaptic DOR of a key synaptic activity altered by morphine, thus implying likely important involvement of DOR in opioid reward and addiction.