A Novel Neuroimmune Risk Factor for Comorbid Depression and Chronic Pain

描述（由申请人提供）：本申请旨在使用神经免疫方法来理解行为的神经生物学基础。目的是研究神经系统和免疫系统之间的相互作用是如何导致抑郁症和疼痛的共同发病的。抑郁症和慢性疼痛是西方世界的两大健康负担。慢性疼痛易患抑郁症，反之亦然，30 - 60%的病例同时患有抑郁症和慢性疼痛。我们试图用神经免疫方法回答的广泛问题是：为什么慢性疼痛是抑郁症的危险因素，反之亦然？外周炎症导致疾病行为，当色氨酸代谢酶2，3吲哚胺双加氧酶（IDO）上调时，疾病行为可最终导致抑郁行为。我们最近取得了令人兴奋的发现，即称为G蛋白偶联受体激酶2（GRK2）的细胞内蛋白具有抗炎特性，并作为调节从急性疼痛到慢性疼痛转变的分子开关。我们最新的初步数据表明，低GRK2增强IDO表达的小胶质细胞在体外。这项提案将测试一个全新的概念，即GRK2是一种关键分子，可以解释抑郁症和慢性疼痛的共同风险。我们已经表明，慢性神经性疼痛或炎症显著减少啮齿动物小胶质细胞中的GRK2。这一发现在临床上是重要的，因为小胶质细胞中的低GRK2足以将短暂的炎性疼痛转化为慢性疼痛。我们还表明，低GRK2增强促炎细胞因子的产生，并增加体内和体外p38的激活。此外，我们有初步数据表明，p38活性调节IDO表达，这是炎症相关抑郁样行为发展的关键。我们推测，慢性神经病理性疼痛引起的小胶质细胞GRK2的减少增加了小胶质细胞p38的活性，促炎细胞因子的产生和IDO的表达，从而作为延长抑郁样和疼痛行为的危险因素。为了验证这一假设，我们将回答以下具体问题：1。神经病理性疼痛和抑郁样行为的发生是否与炎症诱导的GRK2减少和CNS小胶质细胞/mf中IDO增加有时间关系？2.低GRK2是抑郁样行为发展的危险因素吗？其机制是什么？我们将使用我们使用Cre-Lox技术产生的小胶质细胞中GRK2低的小鼠。3.通过干预GRK2减少、p38活性增加和IDO上调的循环，是否可以预防共病抑郁症和慢性疼痛？总的来说，这些创新实验将确定低GRK2作为通过p38/细胞因子/IDO依赖性途径发展共病抑郁症和慢性疼痛的全新风险因素。这些新的分子机制的识别共病抑郁症和疼痛的有效发展的新的预防和治疗策略是必要的。 公共卫生相关性：这项研究对公共卫生具有重要意义，因为我们预计会发现与神经损伤相关的慢性疼痛和抑郁症的一种新的共同神经免疫风险因素。关键是一种称为G蛋白偶联受体激酶-2的酶。介导低GRK2作为抑郁症和疼痛的主要风险因素的作用的神经免疫途径的描绘最终有望开发旨在治疗这些频繁并发疾病的原因的新治疗策略。这项拟议中的研究可能会对国家神经疾病和中风研究所的使命产生重大影响，即减轻包括慢性疼痛在内的神经疾病的负担。

DESCRIPTION (provided by applicant): The present application aims at using neuroimmune approaches to understand the neurobiological basis of behavior. The objective is to study how deregulated interactions between the nervous and immune systems contribute to co morbidity of depression and pain. Depressive disorders and chronic pain represent two major health burdens in the Western world. Chronic pain predisposes to depression and vice versa, and 30-60% of the cases suffer from both depression and chronic pain. The broad question we seek to answer using a neuroimmune approach is: Why is chronic pain a risk factor for depression, and vice versa? Peripheral inflammation causes sickness behavior that can culminate into depressive behavior when the tryptophan metabolizing enzyme 2,3 indoleamine dioxygenase (IDO) is up regulated. We recently made the exciting discovery that an intracellular protein known as G protein coupled receptor kinase 2 (GRK2) possesses anti-inflammatory properties and acts as a molecular switch that regulates transition from acute to chronic pain. Our newest preliminary data indicate that low GRK2 enhances IDO expression by microglia in vitro. This proposal will test the completely novel concept that GRK2 is a critical molecule that explains the shared risk for developing depression and chronic pain. We have shown that chronic neuropathic pain or inflammation significantly reduces GRK2 in microglia from rodents. This finding is clinically important because low GRK2 in microglia is sufficient to transform transient inflammatory pain into chronic pain. We also showed that low GRK2 augments pro-inflammatory cytokine production and increases activation of p38 in vivo and in vitro. Moreover, we have preliminary data that p38 activity regulates IDO expression, which is key to development of inflammation-associated depressive-like behavior. We hypothesize that the reduction in microglial GRK2 caused by chronic neuropathic pain increases microglial p38 activity, pro-inflammatory cytokine production and IDO expression, thereby acting as risk factor for prolonged depressive-like and pain behaviors. To test this hypothesis, we will answer the following specific questions: 1. Is development of neuropathic pain and depressive-like behavior temporally related to the inflammation-induced reduction in GRK2 and the increase in IDO in CNS microglia/mf? 2. Is low GRK2 a risk factor for development of depressive-like behaviors and what is the mechanism? We will use mice with low GRK2 in microglia that we have generated using Cre-Lox technology. 3. Are comorbid depression and chronic pain both prevented by treatments that interfere with the loop of reduced GRK2, increase in p38 activity and upregulation of IDO? Collectively, these innovative experiments will identify low GRK2 as a completely novel risk factor for development of comorbid depression and chronic pain via a p38/cytokine/IDO-dependent pathway. Identification of these new molecular mechanisms underlying comorbid depression and pain is needed for effective development of novel prevention and therapeutic strategies. PUBLIC HEALTH RELEVANCE: The proposed research is relevant and significant for public health because we anticipate discovering a novel shared neuroimmune risk factor for chronic pain and depression associated with nerve injury. The key is an enzyme known as G protein coupled receptor kinase-2. Delineation of neuroimmune pathways that mediate the effect of low GRK2 as a major risk factor in depression and pain is ultimately expected to enable development of novel therapeutic strategies aimed at treating the cause of these frequently co-occurring disorders. The proposed research is likely to have a major impact on the mission of the National Institute of Neurological Disorders and Stroke that is to reduce the burden of neurological disorders, including chronic pain.