Forensic Department, Xi'an Jiaotong University School of Medicine, 76# West Yanta Road, Xi'an 710061, PR China.
Neurosci Lett. 2010 Jan 14;468(3):348-52. doi: 10.1016/j.neulet.2009.11.030. Epub 2009 Nov 14.
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.
丝裂原活化蛋白激酶（MAPK）可被吗啡等阿片类药物通过阿片受体激活，其激活已在突触可塑性、学习、记忆和成瘾中观察到。长期暴露于吗啡可能会导致身体依赖，当药物被剥夺时，会表现出躯体戒断症状，如腹泻、体重减轻、跳跃和摇头。尽管吗啡依赖和戒断已经被广泛研究，但它们的分子机制尚未完全阐明。在本研究中，通过间歇性递增吗啡注射程序在小鼠中建立吗啡身体依赖，并通过体重减轻和行为迹象（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，慢性给予吗啡的小鼠经历了明显的体重减轻。与自发戒断相比，纳洛酮诱发的戒断导致更多的体重减轻。与自发戒断小鼠相比，纳洛酮诱发戒断的小鼠表现出明显加重的吗啡戒断症状（包括跳跃和摇头）。研究了前额联合皮层（FrA）、伏隔核（Acb）和尾壳核（CPu）中的 MAPK 通路活性，以探讨吗啡依赖和戒断的分子机制。与生理盐水处理的小鼠相比，吗啡依赖小鼠和自发戒断小鼠，纳洛酮诱发戒断的小鼠在 FrA 和 Acb 中 ERK 磷酸化显著增加，但在 CPu 中没有增加。然而，在慢性吗啡依赖和戒断阶段，MAPK 通路中的其他蛋白激酶，包括 p38 和 JNK 的活性，在 FrA、Acb 和 CPu 中没有变化。这些结果表明，FrA 和 Acb 中的 ERK 磷酸化可能与纳洛酮诱发的戒断综合征有关。
