Naloxone-precipitated withdrawal enhances ERK phosphorylation in prefrontal association cortex and accumbens nucleus of morphine-dependent mice
Naloxone-precipitated withdrawal enhances ERK phosphorylation in prefrontal association cortex and accumbens nucleus of morphine-dependent mice
复制标题
纳洛酮诱发戒断增强吗啡依赖性小鼠前额叶联合皮层和伏核中的 ERK 磷酸化
DOI：
10.1016/j.neulet.2009.11.030
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发表时间：
2010-01-14
影响因子：
2.5
通讯作者：
Li, Sheng-bing
中科院分区：
文献类型：
--
作者：
Li, Tao;Hou, Ying;Li, Sheng-bing
丝裂原活化蛋白激酶（Mitogen-activated protein kinases，MAPK）可被吗啡等阿片类药物通过阿片受体激活，在突触可塑性、学习、记忆和成瘾等方面有重要作用。长期接触吗啡可产生身体依赖，当药物被剥夺时，表现为腹泻、体重减轻、跳跃和摇头等躯体戒断症状。虽然吗啡依赖和戒断已被广泛研究，但其分子机制尚未完全阐明。在本研究中，通过间歇性、递增性注射吗啡的方法建立小鼠对吗啡的身体依赖性，并通过体重减轻和行为体征（跳跃和摇头）来测量。我们发现，与生理盐水处理的对照组相比，长期给予吗啡的小鼠经历了显着的体重减轻。与自发戒断相比，纳洛酮催促戒断导致更多的体重减轻。与自发戒断小鼠相比，纳洛酮催促戒断小鼠表现出明显加重的吗啡戒断症状（包括跳跃和头摇）。为探讨吗啡依赖和戒断的分子机制，研究了额叶联合皮层（FrA）、中脑核（Acb）和尾壳核（CPu）MAPK通路的活性。与生理盐水处理小鼠、吗啡依赖小鼠和自发戒断小鼠相比，纳洛酮催促戒断小鼠的FrA和Acb中ERK磷酸化水平显著升高，而CPu中ERK磷酸化水平无明显变化。而MAPK通路中的其他蛋白激酶，包括p38和JNK的活性在吗啡依赖和戒断过程中均无明显变化。这些结果表明，ERK磷酸化的FrA和Acb可能与纳洛酮催促戒断综合征。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
Mitogen-activated protein kinases (MAPK) can be activated by opioids such as morphine via opioid receptor, and their activations have been observed in synaptic plasticity, learning, memory and addiction. Long-term exposure to morphine may induce physical dependence, manifested as somatic withdrawal symptoms such as diarrhea, body weight loss, jumping and headshaking, when drug is deprived. Though morphine dependence and withdrawal have been extensively studied, their molecular mechanisms have not been fully elucidated. In the present study, the physical dependence on morphine was developed in mice by an intermittent, escalating procedure of morphine injections, and was measured by the body weight loss and the behavioral signs (jumping and headshaking). We found that the mice with chronic morphine administration experienced dramatic body weight loss, compared with the saline-treated controls. Naloxone-precipitated withdrawal led to more body weight loss, compared with spontaneous withdrawal. Naloxone-precipitated withdrawal mice showed significantly aggravated morphine-withdrawal symptoms (including jumping and heading shaking), compared with spontaneous withdrawal mice. MAPK pathway activities in the frontal association cortex (FrA), accumbens nucleus (Acb) and caudate putamen (CPu) were examined to probe into molecular mechanism for morphine dependence and withdrawal. Compared with saline-treated mice, morphine-dependent mice and spontaneous withdrawal mice, naloxone-precipitated withdrawal mice showed a significantly increased ERK phosphorylation in FrA and Acb, but not in CPu. However, the activities of other protein kinases in the MAPK pathway, including p38 and JNK, showed no changes in FrA, Acb and CPu of the mice during the chronic morphine dependence and withdrawal phases. These results suggest that the ERK phosphorylation in FrA and Acb may be associated with naloxone-precipitated withdrawal syndrome. (C) 2009 Elsevier Ireland Ltd. All rights reserved.