文章基本信息

标题：RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states
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作者：Vasiliki Mitsi ; Dimitra Terzi ; Immanuel Purushothaman 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：36
页码：E5088-E5097
DOI：10.1073/pnas.1504283112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceNeuropathic pain is a complex disorder, characterized by affective and sensory symptoms. Efficient treatment of this condition should target both pain-modulating pathways and mood/affect networks. We show that tricyclic antidepressants (TCAs), which modulate spinal pain processing, also act in the brain reward center to alleviate allodynia and depression-like behaviors. We reveal how one key protein of nucleus accumbens (NAc)-specific signaling affects several molecules/pathways with emerging roles in antinociceptive and antidepressant mechanisms. Our study provides information about the cellular adaptations induced by TCAs in the NAc and novel targets for pain treatment. The striatal protein Regulator of G-protein signaling 9-2 (RGS9-2) plays a key modulatory role in opioid, monoamine, and other G-protein-coupled receptor responses. Here, we use the murine spared-nerve injury model of neuropathic pain to investigate the mechanism by which RGS9-2 in the nucleus accumbens (NAc), a brain region involved in mood, reward, and motivation, modulates the actions of tricyclic antidepressants (TCAs). Prevention of RGS9-2 action in the NAc increases the efficacy of the TCA desipramine and dramatically accelerates its onset of action. By controlling the activation of effector molecules by G protein and {beta}{gamma} subunits, RGS9-2 affects several protein interactions, phosphoprotein levels, and the function of the epigenetic modifier histone deacetylase 5, which are important for TCA responsiveness. Furthermore, information from RNA-sequencing analysis reveals that RGS9-2 in the NAc affects the expression of many genes known to be involved in nociception, analgesia, and antidepressant drug actions. Our findings provide novel information on NAc-specific cellular mechanisms that mediate the actions of TCAs in neuropathic pain states.
关键词：desipramine ; duloxetine ; HDAC5 ; spared nerve injury ; gene expression