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。目的是研究神经和免疫系统之间失调的相互作用如何导致抑郁和疼痛的共病。抑郁症和慢性疼痛是西方世界的两大健康负担。慢性疼痛容易导致抑郁，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一个广泛问题是：为什么慢性疼痛是抑郁症的一个风险因素，反之亦然？当色氨酸代谢酶2,3吲哚胺双加氧酶（IDO）上调时，外周炎症会导致疾病行为，最终导致抑郁行为。我们最近发现了一种令人兴奋的细胞内蛋白，称为G蛋白偶联受体激酶2 （GRK2）具有抗炎特性，并作为调节从急性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可增强体外小胶质细胞IDO的表达。这一提议将测试一个全新的概念，即GRK2是解释抑郁症和慢性疼痛共同风险的关键分子。我们已经证明慢性神经性疼痛或炎症会显著降低啮齿动物小胶质细胞中的GRK2。这一发现具有重要的临床意义，因为小胶质细胞中GRK2水平低足以将暂时性炎性疼痛转化为慢性疼痛。我们还发现，在体内和体外，低GRK2增加了促炎细胞因子的产生，增加了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。我们假设慢性神经性疼痛引起的小胶质细胞GRK2的减少增加了小胶质细胞p38活性、促炎细胞因子的产生和IDO的表达，从而成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。神经性疼痛和抑郁样行为的发展是否与炎症诱导的GRK2减少和中枢神经系统小胶质细胞/mF中IDO增加有暂时关系？2. 低GRK2是抑郁样行为发生的危险因素吗？其机制是什么？我们将在使用Cre-Lox技术生成的小胶质细胞中使用低GRK2小鼠。3. 通过干预GRK2降低回路、p38活性增加和IDO上调，是否可以预防共病性抑郁和慢性疼痛？总的来说，这些创新的实验将通过p38/细胞因子/ ido依赖途径确定低GRK2是抑郁症和慢性疼痛共病发展的全新危险因素。为了有效地开发新的预防和治疗策略，需要确定这些新的抑郁和疼痛共病的分子机制。

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 dysregulated interactions between the nervous and immune systems contribute to comorbidity 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 upregulated. 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.