Ko Shanelle W, Jia Yongheng, Xu Hui, Yim Se-Jeong, Jang Dong-Hyuk, Lee Yong-Seok, Zhao Ming-Gao, Toyoda Hiroki, Wu Long-Jun, Chatila Talal, Kaang Bong-Kiun, Zhuo Min
Department of Physiology, Faculty of Medicine, University of Toronto, University of Toronto Centre for the Study of Pain, 1 King's College Circle, Medical Sciences Building Rm3342, Toronto, Canada, M5S 1A8.
Eur J Neurosci. 2006 Apr;23(8):2158-68. doi: 10.1111/j.1460-9568.2006.04748.x.
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 micro-opioid receptor between groups. Morphine-treated CaMKIV-KO mice showed less G-protein uncoupling from the micro-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.
环磷酸腺苷反应元件结合蛋白（CREB）是一种参与学习、记忆和药物成瘾的转录因子，可被钙/钙调蛋白依赖性蛋白激酶IV（CaMKIV）磷酸化。在此，我们发现，慢性给予吗啡后，CaMKIV基因敲除（KO）小鼠产生的镇痛耐受性较低，而其身体依赖性或急性吗啡诱导的镇痛作用没有改变。慢性给予吗啡后，野生型小鼠中观察到的磷酸化CREB表达增加在CaMKIV-KO小鼠中未出现，而两组之间微阿片受体的表达或磷酸化没有差异。与野生型小鼠相比，吗啡处理的CaMKIV-KO小鼠中G蛋白与微阿片受体的解偶联较少，而在对照野生型和KO小鼠中解偶联相似。此外，慢性吗啡暴露后，CaMKIV-KO小鼠中吗啡对抑制性传递的降低程度大于对照组。我们的结果为CaMKIV在阿片类镇痛耐受性而非身体依赖性的发展中的作用提供了新证据。
