Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria.
Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria.
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发表时间：
2007
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通讯作者：
M. Bruchas;Benjamin B. Land;Megumi Aita;Mei Xu;Sabiha K. Barot;Shuang Li;C. Chavkin
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作者：
M. Bruchas;Benjamin B. Land;Megumi Aita;Mei Xu;Sabiha K. Barot;Shuang Li;C. Chavkin
介导人类应激性烦躁和啮齿类动物条件性位置厌恶的分子机制尚不清楚。在这里，我们表明，反复游泳应激引起激活κ-阿片受体（KOR）和p38丝裂原活化蛋白激酶（MAPK）共表达的GABA能神经元在丘脑核，皮层和海马。使用针对活化的κ受体（KOR-P）和针对磷酸化-p38 MAPK的磷酸化选择性抗体使活化位点可视化。令人惊讶的是，游泳应激暴露引起的P-p38-IR的增加是完全KOR依赖性的; P-p38-IR在经历相同游泳范例的KOR（-/-）敲除小鼠或用KOR拮抗剂norbinaltorphimine预处理的野生型小鼠中没有增加。为了了解p38激活与KOR激活后的行为效应之间的关系，我们给予p38抑制剂SB 203580 [4-（4-氟苯基）-2-（4-甲磺酰基苯基）-5-（4-吡啶基）-1H-咪唑（i. c. v.）]并发现其选择性地阻断由κ激动剂反式-3，4-二氯-N-甲基-N-[2-（1-吡咯烷基）环己基]-苯乙酰胺（U 50488）引起的条件性位置厌恶和KOR依赖性游泳应激诱导的不动性，而不影响κ阿片镇痛或非选择性地影响联想学习。我们发现，在体内连接KOR和p38激活的机制是一致的，我们以前的体外数据表明，β-抑制蛋白的招聘是必需的;缺乏G-蛋白偶联受体激酶3的小鼠也未能增加p-p38-IR后KOR激活在体内，未能显示游泳应激诱导的不动性，或开发条件性的地方厌恶U 50488。我们的研究结果表明，激活p38 MAPK信号的内源性强啡肽-κ-阿片系统可能构成的分子机制介导的厌恶属性的压力的关键组成部分。
The molecular mechanisms mediating stress-induced dysphoria in humans and conditioned place aversion in rodents are unknown. Here, we show that repeated swim stress caused activation of both kappa-opioid receptor (KOR) and p38 mitogen-activated protein kinase (MAPK) coexpressed in GABAergic neurons in the nucleus accumbens, cortex, and hippocampus. Sites of activation were visualized using phosphoselective antibodies against activated kappa receptors (KOR-P) and against phospho-p38 MAPK. Surprisingly, the increase in P-p38-IR caused by swim-stress exposure was completely KOR dependent; P-p38-IR did not increase in KOR(-/-) knock-out mice subjected to the same swim-paradigm or in wild-type mice pretreated with the KOR antagonist norbinaltorphimine. To understand the relationship between p38 activation and the behavioral effects after KOR activation, we administered the p38 inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)-1H-imidazole (i.c.v.)] and found that it selectively blocked the conditioned place aversion caused by the kappa agonist trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide (U50488) and the KOR-dependent swim stress-induced immobility while not affecting kappa-opioid analgesia or nonselectively affecting associative learning. We found that the mechanism linking KOR and p38 activation in vivo was consistent with our previous in vitro data suggesting that beta-arrestin recruitment is required; mice lacking G-protein-coupled receptor kinase 3 also failed to increase p-p38-IR after KOR activation in vivo, failed to show swim stress-induced immobility, or develop conditioned place aversion to U50488. Our results indicate that activation of p38 MAPK signaling by the endogenous dynorphin-kappa-opioid system likely constitutes a key component of the molecular mechanisms mediating the aversive properties of stress.