Opiate-induced changes in brain adenosine levels and narcotic drug responses.
Opiate-induced changes in brain adenosine levels and narcotic drug responses.
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DOI：
10.1016/j.neuroscience.2012.10.031
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发表时间：
2013-01-03
期刊：
影响因子：
3.3
通讯作者：
Peltz, G.
中科院分区：
文献类型：
--
作者：
Wu, M.;Sahbaie, P.;Zheng, M.;Lobato, R.;Boison, D.;Clark, J. D.;Peltz, G.
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。阿片类药物诱导的脑代谢组学变化可能介导阿片类药物的某些药效学作用。为了研究这一点，阿片类药物诱导的脑代谢组学反应进行了分析，使用半靶向的方法在C57 BL/6和129 Sv 1小鼠，表现出极端的差异，他们的倾向，成为阿片类药物依赖。在4天内给予递增的吗啡剂量（10-40 mg/kg），选择性地诱导C57 BL/6小鼠脑干中腺苷丰度降低2倍（p<0.00005），这些小鼠表现出麻醉药物依赖症状;但在129 Sv 1小鼠中没有降低腺苷丰度，这些小鼠没有表现出依赖症状。基于这一发现，腺苷对依赖性的影响进行了研究，在基因工程小鼠的大脑和药理学实验中腺苷张力的改变。在脑干腺苷张力降低的基因工程小鼠中，以及通过腺苷受体1（A1）激动剂（2-氯-N6-环戊基腺苷，0.5 mg/kg）或A2 a受体（A2 a）拮抗剂（SCH 58261 1 mg/kg）给药，吗啡戒断行为显著减少（P<0.0004）。这些结果表明腺苷稳态在麻醉药物反应中起着至关重要的作用。阿片诱导的脑腺苷水平的变化可以解释与阿片成瘾和戒断相关的许多重要的神经行为特征。
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 two-fold 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 receptor1 (A1) agonist (2-chloro-N6-cyclopentyladenosine, 0.5 mg/kg) or an A2a receptor (A2a) antagonist (SCH 58261 1 mg/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.
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影响因子：
3.6
作者：
COSTALL, B;JONES, BJ;TYERS, MB
通讯作者：
TYERS, MB
影响因子：
8.8
作者：
Gauthier, Elizabeth A.;Guzick, Sarah E.;Lydic, Ralph
通讯作者：
Lydic, Ralph
影响因子：
5
作者：
Kaplan, GB;Coyle, TS
通讯作者：
Coyle, TS
腺苷和睡眠。
影响因子：
5.3
作者：
Bjorness TE;Greene RW
通讯作者：
Greene RW
影响因子：
7.3
作者：
Castane, A.;Wells, L.;Valverde, O.
通讯作者：
Valverde, O.