Neurofilament proteins and cAMP pathway in brains of μ-, δ- or κ-opioid receptor gene knock-out mice:: effects of chronic morphine administration
Neurofilament proteins and cAMP pathway in brains of μ-, δ- or κ-opioid receptor gene knock-out mice:: effects of chronic morphine administration
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DOI：
10.1016/j.neuropharm.2003.10.006
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发表时间：
2004-03-01
影响因子：
4.7
通讯作者：
Maldonado, R
中科院分区：
文献类型：
--
作者：
García-Sevilla, JA;Ferrer-Alcón, M;Maldonado, R
阿片成瘾与神经丝蛋白异常和脑内cAMP信号上调有关，这可能调节神经元的可塑性。这项研究使用缺乏u-阿片受体、β-阿片受体或kappa-阿片受体的基因靶向小鼠，研究了这些受体在调节基础活动中的作用以及吗啡对这两个细胞内靶点的慢性影响。在WT小鼠中，慢性给药(5天)吗啡(20-100 mg/kg)导致大脑皮层神经丝(NF)-L免疫密度下降(14-23%)。相反，慢性吗啡并没有降低Mu-、Delta型和Kappa-KO小鼠大脑皮层中的核因子-L，提示这三种类型的阿片受体参与了吗啡的这种作用。此外，慢性吗啡诱导的WT小鼠磷酸化的NF-H显著增加(两倍)在MU-KO小鼠中被取消。在MU、Delta和K-KO小鼠的皮质和/或纹状体内，Galphai1/2蛋白的基础免疫强度、蛋白激酶A的催化亚型(Calpha)和cAMP反应元件结合蛋白(CREB)的总含量与WT小鼠无差异。相反，磷酸化CREB(该转录因子的活性形式)在MU-KO和Delta-KO小鼠的皮质和/或纹状体(23-26%)中减少，但在Kappa-KO动物中不减少。这些结果表明，作用于Mu/Delta受体的内源性阿片紧张性刺激脑内CREB的激活。在WT小鼠的大脑皮层和/或纹状体，慢性吗啡不能诱导cAMP信号通路主要成分的上调。相反，慢性吗啡治疗MU-KO小鼠，而不是在Delta或K-KO小鼠中，导致大脑皮质和/或纹状体Galphai1/2(12-19%)、PKA(19-21%)和磷酸化CREB(21-73%)的矛盾上调，但不是全部CREB的上调。MU-KO小鼠异源受体适应的诱导可能解释了吗啡的这种矛盾效应。(C)2003爱思唯尔有限公司。保留所有权利。
Opiate addiction is associated with abnormalities of neurofilament (NF) proteins and upregulation of cAMP signaling in the brain, which may modulate neuronal plasticity. This study investigated, using gene-targeted mice lacking mu-, delta- or kappa-opioid receptors, the role of these receptors in modulating the basal activity and the chronic effects of morphine on both intracellular targets. In WT mice, chronic treatment (5 days) with morphine (20-100 mg/kg) resulted in decreases in the immunodensity of neurofilament (NF)-L in the cerebral cortex (14-23%). In contrast, chronic morphine did not decrease NF-L in cortices of mu-, delta-, and kappa-KO mice, suggesting the involvement of the three types of opioid receptors in this effect of morphine. Also, the marked increase in phosphorylated NF-H induced by chronic morphine in WT mice (two-fold) was abolished in mu-KO mice. In cortex and/or striatum of mu-, delta- and K-KO mice, the basal immunodensities of Galphai1/2 proteins, the catalytic isoform (Calpha) of protein kinase A (PKA) and the total content of cAMP response element-binding protein (CREB, the nuclear target of PKA) were not different from those of WT mice. In contrast, phosphorylated CREB (the active form of this transcription factor) was reduced in cortex and/or striatum (23-26%) of mu- and delta-KO mice, but not in kappa-KO animals. These results suggest that the endogenous opioid tone acting on mu-/delta-receptors tonically stimulate CREB activation in the brain. In cortex and/or striatum of WT mice, chronic morphine did not induce upregulation of the main components of the cAMP signaling pathway. In contrast, chronic morphine treatment in mu-KO mice, but not in delta- or K-KO, resulted in a paradoxical upregulation of Galphai1/2 (12-19%), PKA (19-21%,) and phosphorylated CREB (21-73%), but not total CREB, in cortex and/or striatum. The induction of heterologous receptor adaptations in mu-KO mice may explain this paradoxical effect of morphine. (C) 2003 Elsevier Ltd. All rights reserved.