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

慢性疼痛发展过程中下行回路稳态神经免疫相互作用的破坏

• 批准号: 10190898
• 负责人: KE REN
• 金额: $ 60.6万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10190898
• 关键词: Acute; Address; Anatomy; Anterior; Anti-Inflammatory Agents; Attention; Attenuated; Behavioral; Biochemical; Brain; CD 200; CRISPR/Cas technology; Calcium; Cells; Chemicals; Clinical Treatment; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Development; Disease; Disinhibition; Event; Excitatory Synapse; Exhibits; FOXP3 gene; Failure; Gene Deletion; Glutamate Transporter; HTR3A gene; Hippocampus (Brain); Homeostasis; Human; Image; Immune; Immunoglobulins; Immunohistochemistry; Injury; Lead; Measures; Mediating; Mediator of activation protein; Medical; Microglia; Mus; Nerve; Neuraxis; Neuroglia; Neuroimmune; Neurons; Nociception; Nociceptors; Pain; Pain Disorder; Pain management; Pathway interactions; Peripheral; Persistent pain; Pharmacology; Phase; Phenotype; Protein Analysis; RNA; RNA Interference; Regulatory T-Lymphocyte; Role; STAT6 Transcription Factor; Serotonin; Serotonin Receptors 5-HT-3; Signal Pathway; Signal Transduction; Slice; Spinal; Structure; Technology; Temporomandibular Joint Dysfunction Syndrome; Testing; Therapeutic; Transgenic Mice; Trigeminal System; Up-Regulation; Viral; chronic constriction injury; chronic pain; chronic pain management; chronic painful condition; cingulate cortex; designer receptors exclusively activated by designer drugs; dorsal horn; equilibration disorder; immune function; improved; inhibitory neuron; nerve injury; novel; optogenetics; pain sensitivity; painful neuropathy; preclinical study; receptor; two-photon

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.

数百万人患有慢性或持续性疼痛，这是一个重大的医学问题。目前的 慢性疼痛的治疗效果并不令人满意。近年来，已有大量证据证明 神经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中。尽管势不可挡 来自临床前研究的证据表明，使用神经胶质调节剂治疗慢性疼痛的临床试验尚未 之所以能成功，与我们对机制的理解不完全有关。虽然大多数 研究表明，损伤相关的神经胶质活性具有促进疼痛的作用，这是一种潜在的抑制/保护作用 持续性疼痛发生过程中神经元-胶质细胞的相互作用在很大程度上被忽视了。中央 神经系统（CNS）稳态由多种抑制信号通路支持，其中 CD200-CD200R信号串联引起了人们的关注。来自神经元的免疫球蛋白 CD200 通过其信号 小胶质细胞上的受体 CD200R 维持小胶质细胞处于监视状态。 CD200 丢失或减少- 损伤后 CD200R 信号传导促进小胶质细胞激活。 下降通路提供平衡调节以维持正常的疼痛敏感性。协助或 延髓头端腹内侧 (RVM)（下行通路中的一个枢轴结构）的去抑制作用 脊髓/三叉神经背角导致慢性疼痛的发生。我们的初步结果表明 从前扣带皮层 (ACC) 直接投射到 RVM 的新下行通路 参与 5-HT3 受体 (5-HT3R) 依赖性疼痛促进。其背后的细胞机制 这种直接 ACC-RVM 连接的功能尚不清楚。 我们建议分析新型 ACC-RVM 下行疼痛中抑制/有益神经胶质细胞的相互作用 调节电路并测试破坏抑制性神经胶质细胞活性有助于出现的假设 慢性疼痛。我们的工作假设是 CNS CD200-CD200R 信号轴对于 体内平衡和信号传导不足/中断会扰乱平衡并导致慢性疼痛 状况。 目标 1 将检验以下假设：新的 ACC-RVM 通路对疼痛的促进作用不足 稳态 CD200-CD200R 信号传导和含 5-HT 神经元的过度兴奋。目标 2 将测试 假设 RVM 中抑制性 CD200-CD200R 信号传导的破坏导致了 慢性疼痛。目标 3 将检验以下假设：CD200/CD200R 信号传导对于抗- RVM 中小胶质细胞的炎症表型，涉及下游叉头盒 P3 (Foxp3) 和信号 转录转导子和转录激活子 6 (STAT6) 活性。 探索神经胶质活动的有益作用将填补我们理解上的空白，并带来变革性的结果 寻求改善慢性疼痛管理的转变。