Molecular mechanisms in dizocilpine-induced attenuation of development of morphine dependence:: an association with cortical Ca2+/calmodulin-dependent signal cascade
Molecular mechanisms in dizocilpine-induced attenuation of development of morphine dependence:: an association with cortical Ca2+/calmodulin-dependent signal cascade
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DOI：
10.1016/j.bbr.2003.10.014
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发表时间：
2004-07-09
影响因子：
2.7
通讯作者：
Nabeshima, T
中科院分区：
文献类型：
--
作者：
Hamdy, MM;Noda, Y;Nabeshima, T
我们研究了地佐西平（一种非竞争性 N-甲基-D-天冬氨酸 (NMDA) 受体拮抗剂）如何影响小鼠吗啡依赖的发展。地佐西平 (0.25 mg/kg) 和吗啡 (10 mg/kg) 联合给药 5 天可减弱吗啡抗伤害作用的耐受性。与用吗啡和盐水治疗的小鼠相比，用地佐西平和吗啡联合治疗的小鼠中由纳洛酮挑战（5 mg/kg）诱导的戒断表现显着减少。本研究揭示了纳洛酮诱发戒断综合征的小鼠皮质和丘脑中 c-Fos 蛋白表达显着增加。地佐环平和吗啡的组合可阻止皮质和丘脑中 c-Fos 蛋白表达的增加。有趣的是，地佐西平和吗啡的重复联合给药可以防止戒断诱导的皮质中 Ca2+/钙调蛋白激酶 II (p-CaMK II) 的磷酸化，但不能防止丘脑中的磷酸化。纳洛酮攻击前的急性地佐西平治疗和单独重复地佐西平治疗对镇痛、戒断症状、p-CaMK II 水平或 c-Fos 蛋白水平没有影响。这些结果表明，地佐西平和吗啡的共同给药可防止吗啡耐受和依赖性的发展，并表明地佐西平的预防作用是由于c-Fos蛋白表达的调节所致，c-Fos蛋白表达可能与皮质中Ca2+/钙调蛋白依赖性信号级联的激活有关。 (C) 2003 Elsevier B.V. 保留所有权利。
We investigated how dizocilpine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, affects the development of morphine dependence in mice. Co-administration of dizocilpine (0.25 mg/kg) and morphine (10 mg/kg) for 5 days attenuated the development of tolerance to the antinociceptive effects of morphine. The withdrawal manifestation induced by the naloxone-challenge (5 mg/kg) was significantly reduced in mice that were treated with a combination of dizocilpine and morphine, compared to the mice treated with morphine and saline. The present study revealed a significant increase in c-Fos protein expression in the cortex and thalamus of mice showing naloxone-precipitated withdrawal syndrome. The combination of dizocilpine and morphine prevented the increase of c-Fos protein expression in the cortex and thalamus. Interestingly, repeated co-administration of dizocilpine and morphine prevented the withdrawal-induced phosphorylation of Ca2+/calmodulin kinase II (p-CaMK II) in the cortex, but not in the thalamus. Acute dizocilpine treatment prior to the naloxone-challenge and repeated treatment with dizocilpine alone had no effect on analgesia, withdrawal manifestations, p-CaMK II levels or c-Fos protein levels. These results showed that co-administration of dizocilpine and morphine prevented the development of morphine tolerance and dependence and suggested that the preventive effect of dizocilpine results from the regulation of c-Fos protein expression, which is possibly involved in the activation of the Ca2+/calmodulin-dependent signal cascade in the cortex. (C) 2003 Elsevier B.V. All rights reserved.