Disruption of Homeostatic Neuroimmune Interactions in Descending Circuitry in the Development of Pain Chronicity

数百万人患有慢性或持续性疼痛，这是一个主要的医疗问题。当前 对慢性疼痛病症的治疗是不令人满意的。近年来，大量证据表明， 胶质细胞的作用及其与神经元的相互作用在持续性疼痛的发展。尽管有压倒性 来自临床前研究的证据表明，用神经胶质调节剂治疗慢性疼痛的临床试验还没有 这与我们对机制的认识不全面有关。虽然大多数 研究表明，与损伤相关的神经胶质活性的疼痛促进方面， 神经元-神经胶质细胞在持续性疼痛发展中的相互作用在很大程度上被忽视。中央 神经系统（CNS）的稳态由多种抑制性信号通路支持，其中， CD200-CD200R信号串联体引起了人们的关注。来自神经元的免疫球蛋白CD200通过其 受体CD200R，以维持小胶质细胞处于监视状态。CD200丧失或减少- 损伤后CD200 R信号转导促进小胶质细胞活化。 下行通路提供平衡的调节以维持正常的疼痛敏感性。便利或 从延髓头端腹内侧（RVM）（下行通路中的枢纽结构）到 脊髓/三叉神经背角有助于慢性疼痛的发展。我们的初步结果表明， 新的下行通路从前扣带皮层（ACC）直接投射到RVM， 参与5-HT3受体（5-HT3R）依赖性疼痛易化。细胞机制的基础， 这种直接ACC-RVM连接的功能尚不清楚。 我们建议分析新的ACC-RVM下行疼痛中抑制/有益的神经胶质细胞相互作用 调制电路和测试的假设，破坏抑制神经胶质细胞的活动有助于出现 慢性疼痛。我们的工作假设是CNS CD200-CD200R信号传导轴是必需的， 内稳态和信号传导不足/中断，干扰平衡并导致慢性疼痛 条件 目的1将检验新的ACC-RVM通路的疼痛易化涉及不充分的 稳态CD200-CD200R信号传导和含5-HT神经元的过度兴奋性。目标2将测试 RVM中抑制性CD200-CD200 R信号传导被破坏的假说有助于 慢性疼痛目的3将检验CD200/CD200R信号传导对于抗-CD200抗体的重要性的假设。 RVM中小胶质细胞的炎症表型，并涉及下游叉头盒P3（Foxp3）和信号转导 转导子和转录激活子6（STAT6）活性。 探索神经胶质活性的有益作用将填补我们认识上的差距，并导致一个变革性的 寻求改善慢性疼痛管理的转变。

Millions of people suffer from chronic or persistent pain, which is a major medical problem. The current treatment for chronic pain conditions is unsatisfactory. In recent years, ample evidence has documented the role of glia and their interactions with neurons in the development of persistent pain. Despite overwhelming evidence from preclinical studies, clinical trials for the treatment of chronic pain with glial modulators have not been successful, which is related to our incomplete understanding of the mechanisms. While a majority of studies show the pain-facilitating aspect of the injury-related glial activity, a potential inhibitory/protective role of neuron-glial interactions in the development of persistent pain has been largely overlooked. The central nervous system (CNS) homeostasis is supported by multiple inhibitory signaling pathways, among which the CD200-CD200R signaling tandem has attracted attention. Immunoglobulin CD200 from neurons signals via its receptor CD200R on microglia to maintain microglia at the surveillance state. Loss of or reduced CD200- CD200R signaling after injury facilitates microglial activation. Descending pathways provide balanced modulation to maintain normal pain sensitivity. Facilitation or disinhibition from the rostral ventromedial medulla (RVM), a pivot structure in descending pathways, to the spinal/ trigeminal dorsal horn contributes to the development of chronic pain. Our preliminary results point to a new descending pathway from the anterior cingulate cortex (ACC) that directly projects to the RVM and is involved in the 5-HT3 receptor (5-HT3R)-dependent pain facilitation. The cellular mechanisms underlying the function of this direct ACC-RVM connection is unclear. We propose to analyze inhibitory/beneficial neuroglial interactions in the novel ACC-RVM descending pain modulatory circuitry and test the hypothesis that disrupted inhibitory glial activity contributes to the emergence of chronic pain. Our working hypothesis is that the CNS CD200-CD200R signaling axis is necessary for homeostasis and insufficient/disrupted signaling of which disturbs the balance and contributes to chronic pain conditions. Aim 1 will test the hypothesis that pain facilitation from the novel ACC-RVM pathway involves insufficient homeostatic CD200-CD200R signaling and hyperexcitability of 5-HT-containing neurons. Aim 2 will test the hypothesis that disrupted inhibitory CD200-CD200R signaling in the RVM contributes to the emergence of chronic pain. Aim 3 will test the hypothesis that the CD200/CD200R signaling is important for the anti- inflammatory phenotype of microglia in the RVM and involves downstream forkhead box P3 (Foxp3) and signal transducer and activator of transcription 6 (STAT6) activity. Exploring the beneficial effect of glial activity will fill the gap in our understanding and lead to a transformative shift in the search for improved management for chronic pain.