Morphine-induced analgesic tolerance, locomotor sensitization and physical dependence do not require modification of mu opioid receptor, cdk5 and adenylate cyclase activity
Morphine-induced analgesic tolerance, locomotor sensitization and physical dependence do not require modification of mu opioid receptor, cdk5 and adenylate cyclase activity
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DOI：
10.1016/j.neuropharm.2007.10.015
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发表时间：
2008-03-01
影响因子：
4.7
通讯作者：
Kieffer, Brigitte L.
中科院分区：
文献类型：
--
作者：
Contet, Candice;Filliol, Dorninique;Kieffer, Brigitte L.
急性吗啡给药产生镇痛和奖励，但长期使用可能导致慢性疼痛治疗患者的镇痛耐受和阿片类药物成瘾者的强迫性摄入。此外，长期接触可能诱发身体依赖，在没有药物的情况下表现为躯体戒断症状。我们建立了三种行为范式来模拟小鼠的这些适应，使用不同的重复吗啡注射方案来诱导镇痛耐受、运动致敏或身体依赖。有趣的是，对镇痛耐受的小鼠对过度运动不敏感，而对过度运动敏感的小鼠表现出一定的镇痛耐受。然后，我们检查了可能成为每种行为适应发展基础的候选分子修饰。首先，在导水管周围灰质中，镇痛耐受性不伴有mu阿片受体脱敏。其次，运动致敏小鼠尾壳核、伏隔核和前额叶皮层的cdk5和p35蛋白水平没有变化。最后，纳洛酮沉淀的吗啡戒断并没有增强伏隔核、前额叶皮层、杏仁核、终纹床核或导管周围灰质中基底或福斯克林刺激的腺苷酸环化酶活性。因此，慢性吗啡治疗的行为适应表达与相关脑区mu阿片受体、cdk5或腺苷酸环化酶活性的调节无关。虽然我们不能排除在我们的实验条件下没有检测到这些修饰，但另一种假设是，尚未发现的其他分子机制是慢性吗啡给药诱导的镇痛耐受性、运动致敏和身体依赖的基础。(c) 2007 Elsevier Ltd.版权所有。
Acute morphine administration produces analgesia and reward, but prolonged use may lead to analgesic tolerance in patients chronically treated for pain and to compulsive intake in opioid addicts. Moreover, long-term exposure may induce physical dependence, manifested as somatic withdrawal symptoms in the absence of the drug. We set up three behavioral paradigms to model these adaptations in mice, using distinct regimens of repeated morphine injections to induce either analgesic tolerance, locomotor sensitization or physical dependence. Interestingly, mice tolerant to analgesia were not sensitized to hyperlocomotion, whereas sensitized mice displayed some analgesic tolerance. We then examined candidate molecular modifications that could underlie the development of each behavioral adaptation. First, analgesic tolerance was not accompanied by mu opioid receptor desensitization in the periaqueductal gray. Second, cdk5 and p35 protein levels were unchanged in caudate-putamen, nucleus accumbens and prefrontal cortex of mice displaying locomotor sensitization. Finally, naloxone-precipitated morphine withdrawal did not enhance basal or forskolin-stimulated adenylate cyclase activity in nucleus accumbens, prefrontal cortex, amygdala, bed nucleus of stria terminalis or periaqueductal gray. Therefore, the expression of behavioral adaptations to chronic morphine treatment was not associated with the regulation of mu opioid receptor, cdk5 or adenylate cyclase activity in relevant brain areas. Although we cannot exclude that these modifications were not detected under our experimental conditions, another hypothesis is that alternative molecular mechanisms, yet to be discovered, underlie analgesic tolerance, locomotor sensitization and physical dependence induced by chronic morphine administration. (c) 2007 Elsevier Ltd. All rights reserved.