Distinct expression of synaptic NR2A and NR2B in the central nervous system and impaired morphine tolerance and physical dependence in mice deficient in postsynaptic density-93 protein.
Distinct expression of synaptic NR2A and NR2B in the central nervous system and impaired morphine tolerance and physical dependence in mice deficient in postsynaptic density-93 protein.
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突触NR2A和NR2B在中枢神经系统中的明显表达，并在突触后密度93蛋白缺乏小鼠中的吗啡耐受性和身体依赖性受损。
DOI：
10.1186/1744-8069-4-45
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发表时间：
2008-10-14
期刊：
影响因子：
3.3
通讯作者：
Tao, Yuan-Xiang
中科院分区：
文献类型：
--
作者：
Liaw, Wen-Jinn;Zhu, Xu-Guang;Yaster, Myron;Johns, Roger A.;Gauda, Estelle B.;Tao, Yuan-Xiang
突触后致密物（Postsynaptic density，PSD）-93是一种神经元支架蛋白，在体外可与N-甲基-D-天冬氨酸受体（NMDAR）亚基NR 2A和NR 2B结合并聚集在细胞膜上。然而，PSD-93在中枢神经系统中的突触NR 2A和NR 2B靶向以及NMDAR依赖的生理和病理过程中的作用仍然不清楚。我们在这里报告说，PSD-93缺陷显着减少NR 2A和NR 2B的量的突触体膜馏分来自脊髓背角和前脑皮层，但没有改变其水平的总可溶性馏分从任何一个区域。然而，PSD-93缺陷没有显着改变NR 2A和NR 2B的量在突触体或总可溶性组分从小脑。在PSD-93缺陷的小鼠中，急性和慢性吗啡攻击后，吗啡剂量依赖性曲线没有像野生型（WT）小鼠中那样显著偏移。与WT小鼠不同，PSD-93基因敲除小鼠在重复注射吗啡后，对机械、有害热和福尔马林诱导的炎症刺激的反应中也表现出显著的NMDAR依赖性吗啡镇痛耐受性和相关的异常敏感性损失。此外，PSD-93基因敲除小鼠表现出跳跃活动的显著丧失，这是典型的NMDAR介导的吗啡戒断戒断行为。这些发现表明，PSD-93基因敲除小鼠重复注射吗啡后NMDAR依赖性神经元可塑性受损归因于PSD-93缺失诱导的背角和前脑皮层神经元中突触NR 2A和NR 2B表达的改变。PSD-93缺失对这两个主要疼痛相关区域突触NMDAR表达的选择性影响可能为阿片耐受和身体依赖的预防和治疗提供更好的策略。
Postsynaptic density (PSD)-93, a neuronal scaffolding protein, binds to and clusters N-methyl-D-aspartate receptor (NMDAR) subunits NR2A and NR2B at cellular membranes in vitro. However, the roles of PSD-93 in synaptic NR2A and NR2B targeting in the central nervous system and NMDAR-dependent physiologic and pathologic processes are still unclear. We report here that PSD-93 deficiency significantly decreased the amount of NR2A and NR2B in the synaptosomal membrane fractions derived from spinal cord dorsal horn and forebrain cortex but did not change their levels in the total soluble fraction from either region. However, PSD-93 deficiency did not markedly change the amounts of NR2A and NR2B in either synaptosomal or total soluble fractions from cerebellum. In mice deficient in PSD-93, morphine dose-dependent curve failed to shift significantly rightward as it did in wild type (WT) mice after acute and chronic morphine challenge. Unlike WT mice, PSD-93 knockout mice also showed marked losses of NMDAR-dependent morphine analgesic tolerance and associated abnormal sensitivity in response to mechanical, noxious thermal, and formalin-induced inflammatory stimuli after repeated morphine injection. In addition, PSD-93 knockout mice displayed dramatic loss of jumping activity, a typical NMDAR-mediated morphine withdrawal abstinence behavior. These findings indicate that impaired NMDAR-dependent neuronal plasticity following repeated morphine injection in PSD-93 knockout mice is attributed to PSD-93 deletion-induced alterations of synaptic NR2A and NR2B expression in dorsal horn and forebrain cortex neurons. The selective effect of PSD-93 deletion on synaptic NMDAR expression in these two major pain-related regions might provide the better strategies for the prevention and treatment of opioid tolerance and physical dependence.
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影响因子：
3
作者：
Bhargava, HN;Cao, YJ;Zhao, GM
通讯作者：
Zhao, GM
影响因子：
7.4
作者：
Chu, YC;Guan, Y;Tao, YX
通讯作者：
Tao, YX
影响因子：
16.2
作者：
Elias, Guillermo M.;Funke, Lars;Nicoll, Roger A.
通讯作者：
Nicoll, Roger A.
影响因子：
64.5
作者：
He, L;Fong, J;Whistler, JL
通讯作者：
Whistler, JL
DOI：
10.1073/pnas.96.14.7731
发表时间：
1999-07-06
影响因子：
11.1
作者：
Mayer, DJ;Mao, JR;Price, DD
通讯作者：
Price, DD