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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Kappa Opioid Receptor-Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons
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Kappa Opioid Receptor-Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons

机译：Kappa阿片受体诱导的厌恶需要VTA多巴胺神经元中的p38 MAPK激活

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The endogenous dynorphin-kappa opioid receptor (KOR) system encodes the dysphoric component of the stress response and controls the risk of depression-like and addiction behaviors; however, the molecular and neural circuit mechanisms are not understood. In this study, we report that KOR activation of p38 alpha MAPK in ventral tegmental (VTA) dopaminergic neurons was required for conditioned place aversion (CPA) in mice. Conditional genetic deletion of floxed KOR or floxed p38 alpha MAPK by Cre recombinase expression in dopaminergic neurons blocked place aversion to the KOR agonist U50,488. Selective viral rescue by wild-type KOR expression in dopaminergic neurons of KOR-/-mice restored U50,488-CPA, whereas expression of a mutated form of KOR that could not initiate p38 alpha MAPK activation did not. Surprisingly, while p38 alpha MAPK inactivation blocked U50,488-CPA, p38 alpha MAPK was not required for KOR inhibition of evoked dopamine release measured by fast scan cyclic voltammetry in the nucleus accumbens. In contrast, KOR activation acutely inhibited VTA dopaminergic neuron firing, and repeated exposure attenuated the opioid response. This adaptation to repeated exposure was blocked by conditional deletion of p38 alpha MAPK, which also blocked KOR-induced tyrosine phosphorylation of the inwardly rectifying potassium channel (GIRK) subunit Kir3.1 in VTA dopaminergic neurons. Consistent with the reduced response, GIRK phosphorylation at this amino terminal tyrosine residue (Y12) enhances channel deactivation. Thus, contrary to prevailing expectations, these results suggest that kappa opioid-induced aversion requires regulation of VTA dopaminergic neuron somatic excitability through a p38 alpha MAPK effect on GIRK deactivation kinetics rather than by presynaptically inhibiting dopamine release.
机译：内源性强啡肽-阿片受体（KOR）系统编码应激反应的烦躁不安成分，并控制抑郁症和成瘾行为的风险。然而，分子和神经回路的机制尚不清楚。在这项研究中，我们报告了小鼠腹侧被盖腺（VTA）多巴胺能神经元中p38αMAPK的KOR激活是小鼠条件位置厌恶（CPA）所必需的。在多巴胺能神经元中通过Cre重组酶表达有条件地遗传了FK或p38αMAPK激酶，从而阻止了对KOR激动剂U50,488的厌恶。通过在KOR-/-小鼠的多巴胺能神经元中野生型KOR表达进行选择性病毒抢救可以恢复U50,488-CPA，而不能启动p38αMAPK激活的KOR突变形式则不能。出人意料的是，尽管p38αMAPK失活阻止了U50,488-CPA，但通过伏安核中快速扫描循环伏安法测量的KOR抑制诱发的多巴胺释放，p38αMAPK并不是必需的。相比之下，KOR激活会严重抑制VTA多巴胺能神经元的放电，并且反复接触会减弱阿片类药物的反应。 p38αMAPK的条件缺失阻止了对重复暴露的适应，这也阻止了VOR多巴胺能神经元中KOR诱导的内向整流钾通道（GIRK）亚基Kir3.1酪氨酸磷酸化。与降低的反应一致，在该氨基末端酪氨酸残基（Y12）处的GIRK磷酸化增强了通道的失活。因此，与普遍预期相反，这些结果表明，κ阿片样物质诱导的厌恶需要通过对GIRK失活动力学的p38αMAPK效应而不是先通过先天性抑制多巴胺释放来调节VTA多巴胺能神经元的体细胞兴奋性。

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