Fan G H, Wang L Z, Qiu H C, Ma L, Pei G
Shanghai Institute of Cell Biology, Chinese Academy of Sciences, Shanghai, People's Republic of China.
Mol Pharmacol. 1999 Jul;56(1):39-45. doi: 10.1124/mol.56.1.39.
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.
学习和记忆被认为在阿片类药物成瘾的发展过程中起着重要作用。基于最近的研究发现，钙/钙调蛋白依赖性蛋白激酶II（CaMKII）在学习和记忆过程中至关重要，且吗啡治疗可增加海马体中CaMKII的活性，本研究旨在探讨抑制海马体CaMKII是否能预防吗啡耐受性和依赖性。在此，我们报告，通过向大鼠海马齿状回内注射特异性抑制剂KN-62和KN-93来抑制CaMKII，可显著减弱对吗啡镇痛作用的耐受性以及阿片类拮抗剂纳洛酮引发的戒断综合征。相比之下，KN-62和KN-93的无活性结构类似物KN-04和KN-92未能减弱吗啡耐受性和依赖性，这表明KN-62和KN-93所观察到的效应是通过抑制CaMKII介导的。此外，将CaMKII反义寡核苷酸注射到大鼠海马齿状回中，特异性降低了CaMKII的表达，也减弱了吗啡耐受性和依赖性，而相应的CaMKII正义寡核苷酸则未表现出这种抑制作用。此外，KN-62治疗消除了通过条件性位置偏好测量的吗啡奖赏特性。这些结果表明，海马体CaMKII在吗啡耐受性和依赖性的发展中起关键作用，抑制这种激酶可能在治疗阿片类药物耐受性和依赖性方面具有一定的治疗益处。
