Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305, USA.
Neuroscience. 2013 Jan 3;228:235-42. doi: 10.1016/j.neuroscience.2012.10.031. Epub 2012 Oct 22.
We have very little information about the metabolomic changes that mediate neurobehavioral responses, including addiction. It was possible that opioid-induced metabolomic changes in brain could mediate some of the pharmacodynamic effects of opioids. To investigate this, opiate-induced brain metabolomic responses were profiled using a semi-targeted method in C57BL/6 and 129Sv1 mice, which exhibit extreme differences in their tendency to become opiate dependent. Escalating morphine doses (10-40 mg/kg) administered over a 4-day period selectively induced a twofold decrease (p<0.00005) in adenosine abundance in the brainstem of C57BL/6 mice, which exhibited symptoms of narcotic drug dependence; but did not decrease adenosine abundance in 129Sv1 mice, which do not exhibit symptoms of dependence. Based on this finding, the effect of adenosine on dependence was investigated in genetically engineered mice with alterations in adenosine tone in the brain and in pharmacologic experiments. Morphine withdrawal behaviors were significantly diminished (p<0.0004) in genetically engineered mice with reduced adenosine tone in the brainstem, and by treatment with an adenosine receptor(1) (A(1)) agonist (2-chloro-N6-cyclopentyladenosine, 0.5mg/kg) or an A(2a) receptor (A(2a)) antagonist (SCH 58261, 1mg/kg). These results indicate that adenosine homeostasis plays a crucial role in narcotic drug responses. Opiate-induced changes in brain adenosine levels may explain many important neurobehavioral features associated with opiate addiction and withdrawal.
我们对介导神经行为反应（包括成瘾）的代谢组学变化知之甚少。阿片类药物诱导的大脑代谢组学变化可能介导阿片类药物的一些药效学作用。为了研究这一点，使用半靶向方法在 C57BL/6 和 129Sv1 小鼠中 profiling 阿片类药物诱导的大脑代谢组学反应，这两种小鼠在成为阿片类药物依赖的倾向方面表现出极大的差异。在 4 天内给予递增剂量的吗啡（10-40mg/kg）选择性地使 C57BL/6 小鼠脑干中的腺苷丰度降低了两倍（p<0.00005），这些小鼠表现出麻醉药物依赖的症状；但在不表现出依赖症状的 129Sv1 小鼠中，腺苷丰度并没有降低。基于这一发现，在大脑中腺苷张力发生变化的基因工程小鼠和药理学实验中研究了腺苷对依赖的影响。在大脑中腺苷张力降低的基因工程小鼠中，吗啡戒断行为明显减少（p<0.0004），并且通过用腺苷受体 1（A1）激动剂（2-氯-N6-环戊基腺苷，0.5mg/kg）或 A2a 受体（A2a）拮抗剂（SCH 58261，1mg/kg）治疗。这些结果表明，腺苷动态平衡在麻醉药物反应中起着至关重要的作用。阿片类药物诱导的大脑腺苷水平变化可能解释了许多与阿片类药物成瘾和戒断相关的重要神经行为特征。
