Morphine-induced changes of gene expression in the brain
Morphine-induced changes of gene expression in the brain
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DOI：
10.1080/13556210412331308994
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发表时间：
2005-03-01
影响因子：
3.4
通讯作者：
Höllt, V
中科院分区：
文献类型：
--
作者：
Ammon-Treiber, S;Höllt, V
反复服用鸦片改变了啮齿动物大脑不同区域的基因表达，这一影响可能有助于与成瘾行为相关的可塑性变化。越来越多的证据表明，在吗啡耐受、敏化和戒断过程中，多种转录因子被诱导。尽管吗啡治疗不会导致MU阿片受体(MOR)的表达发生重大变化，但参与iWOR运输的蛋白如GRK2或βarrestin 2存在转录调控，其他受体如多巴胺受体、NMDA受体、GABA(A)受体和α(2A)肾上腺素受体的表达也发生变化。最近的基因表达谱研究揭示了更多的吗啡反应基因簇：虽然单次给药主要是减少与代谢功能有关的基因的表达，但增加吗啡剂量导致吗啡耐受显示诱导了改变突触连接模式的基因，如ARE或ANIA-3。这些基因在快速戒断后仍然升高，这也触发了几个转录激活因子和抑制因子的表达。此外，吗啡被证明是热休克蛋白70的强烈诱导剂，热休克蛋白70是一种细胞保护蛋白，可能会对抗阿片剂诱导的神经毒性。在慢性吗啡应用计划期间的时间表达谱显示，转录因子、G蛋白偶联受体和神经肽等基因簇的离散和波动表达。长时间戒断的特征似乎是几个转录因子上调和配体门控离子通道如谷氨酸和GABA受体亚单位持续下调。这些受体表达的长期变化表明，吗啡治疗后突触信号的持续变化。
Repeated opiate administration alters gene expression in different brain regions of rodents, an effect which may contribute to plastic changes associated with addictive behaviour. There is increasing evidence that multiple transcription factors are induced in morphine tolerance, sensitization and during morphine withdrawal. Whereas morphine treatment does not lead to major alterations in the expression of mu-opioid receptors (MOR), there is transcriptional regulation of proteins involved in iWOR trafficking such as GRK2 or beta arrestin 2 as well as altered expression of other receptors such as dopamine receptors, NMDA receptors, GABA(A) receptor and alpha(2A) adrenoceptor. Recent gene expression profiling studies reveal additional clusters of morphine-responsive genes: whereas single dose administration has been shown to predominantly, reduce expression of genes involved in metabolic function, ascending morphine doses leading to morphine tolerance revealed induction of genes which alter patterns of synaptic connectivity such as are or ania-3. These genes remained elevated after precipitated withdrawal, which also triggered the expression of several transcriptional activators and repressors. In addition, morphine has been shown to be a strong inducer of heat shock protein 70, a cell protective protein which might counter regulate opiate-induced neurotoxicity. Temporal expression profiles during a chronic morphine application schedule revealed discrete and fluctuating expression of gene clusters such as transcription factors, G-protein-coupled receptors and neuropeptides. Prolonged abstinence seems to be characterized by up-regulation of several transcription factors and persistent down-regulation of ligand gated ion channels such as glutamatergic and GABA-ergic receptor subunits. These long-term changes in receptor expression suggest a persistent alteration of synaptic signalling after morphine treatment.