Inhibition of calcium/calmodulin-dependent protein kinase II in rat hippocampus attenuates morphine tolerance and dependence
Inhibition of calcium/calmodulin-dependent protein kinase II in rat hippocampus attenuates morphine tolerance and dependence
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DOI：
10.1124/mol.56.1.39
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发表时间：
1999-07-01
影响因子：
3.6
通讯作者：
Pei, G
中科院分区：
文献类型：
--
作者：
Fan, GH;Wang, LZ;Pei, G
学习和记忆在阿片成瘾的发展中起着重要作用。基于最近的研究发现，钙/钙调素依赖性蛋白激酶II（CaMKII）是必不可少的学习和记忆过程中，和吗啡治疗增加海马CaMKII的活性，本研究进行了检查是否抑制海马CaMKII防止吗啡耐受和依赖。在这里，我们报告说，海马齿状回内给予的特异性抑制剂KN-62和KN-93大鼠的CaMK Ⅱ的抑制显着衰减的耐受性吗啡的镇痛作用和阿片拮抗剂纳洛酮沉淀的戒断综合征。相比之下，KN-62和KN-93的无活性结构类似物KN-04和KN-92均未能减弱吗啡耐受性和依赖性，表明所观察到的KN-62和KN-93的作用是通过抑制CaMKII介导的。此外，在大鼠海马齿状回内给予CaMK Ⅱ反义寡核苷酸，特异性地降低CaMK Ⅱ的表达，也减弱吗啡耐受和依赖，而相应的CaMK Ⅱ正义寡核苷酸没有表现出这种抑制作用。此外，KN-62治疗取消了吗啡的奖励属性所测量的条件性位置偏爱。这些结果表明，海马CaMKII是至关重要的参与吗啡耐受性和依赖性的发展，抑制这种激酶可能有一些治疗阿片类药物耐受性和依赖性的治疗益处。
Learning and memory have been suggested to be important in the development of opiate addiction. Based on the recent findings that calcium/calmodulin-dependent protein kinase II (CaMKII) is essential in learning and memory processes, and morphine treatment increases CaMKII activity in hippocampus, the present study was undertaken to examine whether inhibition of hippocampal CaMKII prevents morphine tolerance and dependence. Here, we report that inhibition of CaMKII by intrahippocampal dentate gyrus administration of the specific inhibitors KN-62 and KN-93 to rats significantly attenuated the tolerance to the analgesic effect of morphine and the abstinence syndrome precipitated by opiate antagonist naloxone. In contrast, both KN-04 and KN-92, the inactive structural analogs of KN-62 and KN-93, failed to attenuate morphine tolerance and dependence, indicating that the observed effects of KN-62 and KN-93 are mediated through inhibition of CaMKII. Furthermore, administration of CaMKII antisense oligonucleotide into rat hippocampal dentate gyrus, which decreased the expression of CaMKII specifically, also attenuated morphine tolerance and dependence, while the corresponding sense oligonucleotide of CaMKII did not exhibit such inhibitory effect. Moreover, the KN-62 treatment abolished the rewarding properties of morphine as measured by the conditioned place preference. These results suggest that hippocampal CaMKII is critically involved in the development of morphine tolerance and dependence, and inhibition of this kinase may have some therapeutic benefit in the treatment of opiate tolerance and dependence.