Evidence for a role of CaMKIV in the development of opioid analgesic tolerance
Evidence for a role of CaMKIV in the development of opioid analgesic tolerance
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DOI：
10.1111/j.1460-9568.2006.04748.x
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发表时间：
2006-04-01
影响因子：
3.4
通讯作者：
Zhuo, M
中科院分区：
文献类型：
--
作者：
Ko, SW;Jia, YH;Zhuo, M
cAMP反应元件结合蛋白（CREB）是一种与学习、记忆和药物成瘾有关的转录因子，被钙-钙调蛋白依赖性蛋白激酶IV（CaMKIV）磷酸化。在这里，我们表明CaMKIV基因敲除（KO）小鼠在长期给予吗啡后产生的镇痛耐受性较低，而身体依赖性或急性吗啡诱导的镇痛没有改变。慢性吗啡后在野生型小鼠中观察到的磷酸化CREB表达的增加在CaMKIV-KO小鼠中不存在，而组间μ阿片受体的表达或磷酸化没有差异。吗啡处理的CaMKIV-KO小鼠显示出较少的G-蛋白解偶联μ阿片受体比野生型小鼠，而解偶联是类似的对照野生型和KO小鼠。此外，吗啡减少抑制传输到更大程度的CaMKIV-KO小鼠比对照组慢性吗啡暴露后。我们的研究结果为CaMKIV在阿片类镇痛耐受性而不是身体依赖性的发展中的作用提供了新的证据。
cAMP response-element binding protein (CREB), a transcription factor involved in learning, memory and drug addiction, is phosphorylated by calcium-calmodulin-dependent protein kinase IV (CaMKIV). Here, we show that CaMKIV-knockout (KO) mice developed less analgesic tolerance after chronic morphine administration with no alteration in physical dependence or acute morphine-induced analgesia. The increase in phosphorylated CREB expression observed in wild-type mice after chronic morphine was absent in CaMKIV-KO mice, while there was no difference in the expression or phosphorylation of the mu-opioid receptor between groups. Morphine-treated CaMKIV-KO mice showed less G-protein uncoupling from the mu-opioid receptor than did wild-type mice, while uncoupling was similar in control wild-type and KO mice. In addition, morphine reduced inhibitory transmission to a greater degree in CaMKIV-KO mice than in controls after chronic morphine exposure. Our results provide novel evidence for the role of CaMKIV in the development of opioid analgesic tolerance but not physical dependence.