Cellular Mechanisms of Antidepressant Drug Actions in Neuropathic Pain Models

描述（由申请人提供）：本项目将阐明抗抑郁药诱导的感觉和情感脑回路介导神经病理性疼痛的信号转导变化。神经性疼痛是一种慢性病症，其特征在于感觉缺陷（机械和冷异常性疼痛、热痛觉过敏）和情绪障碍（焦虑和抑郁）。大多数用于治疗这种疾病的疼痛样症状的药物疗效较低，具有主要的副作用，并且在阿片类药物的情况下可能导致使人衰弱的身体成瘾。因此，迫切需要开发用于治疗慢性神经性疼痛的更有效和更好耐受的药物。三环类抗抑郁药和选择性5-羟色胺/去甲肾上腺素再摄取抑制剂同时具有抗异常性疼痛和抗抑郁特性。然而，长期使用这些药物也会产生严重的不良影响。了解TCAs和SNRIs介导作用的细胞机制将有助于开发新的和更有效的治疗神经性疼痛的药物。我们实验室的初步发现表明，RGS 9 -2，一种有效的纹状体调节因子， GPCR信号幅度和脱敏在TCA的抗异常性疼痛和抗抑郁作用中起着有效的调节作用。我们将使用遗传小鼠模型和基因转移方法来测试我们的假设，即NAc中的RGS 9 -2负调节神经病理性疼痛模型中TCA和SNRI的作用。此外，我们将使用生物化学和分子生物学方法来测试我们对调节TCA和SNRI效应的关键RGS 9 -2蛋白质-蛋白质相互作用以及RGS 9 -2下游响应TCA和SNRI治疗的长期表观遗传变化的假设。最后，我们将在神经性疼痛模型中使用RNA测序来表征抗抑郁剂诱导的和RGS 9 -2调节的全局基因调控。我们的研究结果将阐明NAc中GPCR信号机制调节抗抑郁药物对神经病理性疼痛的感觉和情感症状的影响的机制。

DESCRIPTION (provided by applicant): This project will elucidate antidepressant-induced changes on signal transduction in sensory and affective brain circuitry mediating neuropathic pain. Neuropathic pain is a chronic condition characterized by both sensory deficits (mechanical and cold allodynia, thermal hyperalgesia) and mood disorders (anxiety and depression). Most drugs used to treat the pain-like symptoms of this disorder have low efficacy, carry major side-effects and in the case of opioids may lead to debilitating physical addiction. Thus, there is a pressing need for the development of more efficacious and better tolerated medications for treating chronic neuropathic pain. Tricyclic antidepressants and the selective, serotonin/norepinephrine reuptake inhibitors contain both antiallodynic and antidepressant properties. However, their chronic use is also accompanied by severe adverse effects. Understanding the cellular mechanisms mediating the actions of TCAs and SNRIs will facilitate the development of novel and more efficacious medications for the treatment of neuropathic pain. Preliminary findings from our laboratory indicate that RGS9-2, a potent regulator of striatal GPCR signaling amplitude and desensitization, plays a potent, modulatory role in the antiallodynic and antidepressant actions of TCAs. We will use genetic mouse models and gene transfer approaches to test our hypothesis that RGS9-2 in the NAc negatively regulates the actions of TCAs and SNRIs in neuropathic pain models. In addition, we will use biochemical and molecular biological approaches to test our hypotheses on both the critical RGS9-2 protein-protein interactions modulating the effects of TCA and SNRI and the long-term epigenetic changes downstream of RGS9-2 in response to TCA and SNRI treatment. Finally, we will characterize antidepressant-induced and RGS9-2 modulated global gene regulation using RNA-sequencing in models of neuropathic pain. Our findings will clarify the mechanism by which GPCR signaling machinery in NAc modulates the effects of antidepressant drugs on the sensory and affective symptoms of neuropathic pain.