The role of neuroimmune interactions in the pathogenesis of chronic pain

神经免疫相互作用在慢性疼痛发病机制中的作用

• 批准号: 10451784
• 负责人: MOSES VICTOR CHAO
• 金额: $ 58.6万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451784
• 关键词: Acute; Affect; Affective; Afferent Neurons; Animal Model; Anterior; Area; Astrocytes; Attenuated; Behavioral; Bone Marrow; Brain; Cells; Chronic; Collaborations; Cytokine Receptors; Development; Disease; Etiology; Health; Hyperactivity; Hypersensitivity; Imaging Techniques; Immune; Immune system; Injury; Interferons; Knock-out; Knowledge; Maintenance; Mediating; Microglia; Modeling; Molecular; Mus; Neuroglia; Neuroimmune; Neurons; Pain; Pain management; Pathogenesis; Pathway interactions; Peripheral; Peripheral nerve injury; Persistent pain; Persons; Play; Pre-Clinical Model; Prevention; Process; Production; Research; Role; Sensory; Series; Somatosensory Cortex; Spinal Ganglia; Structure; Synapses; TNF gene; Testing; Tumor Necrosis Factor Receptor; awake; base; behavior test; cell type; chronic neuropathic pain; chronic pain; cingulate cortex; cytokine; debilitating pain; effective therapy; essays; experimental study; genetic manipulation; hippocampal pyramidal neuron; imaging approach; immune activation; in vivo; in vivo calcium imaging; in vivo imaging; in vivo two-photon imaging; innovation; innovative technologies; insight; intense pain; intravital imaging; knockout gene; monocyte; mouse model; nerve injury; neural circuit; new therapeutic target; novel; novel strategies; pain chronification; pain sensation; pain symptom; painful neuropathy; peripheral nerve damage; somatosensory; spared nerve

Project Summary/Abstract Nerve injury-induced neuropathic pain is a major health problem with limited treatment. Insufficient understanding of this disorder at the level of neural circuits impedes the development of effective therapies. The activation of the immune system and neuronal alterations in the somatosensory pathway are known to be critical for the genesis of neuropathic pain. However, how immune cells interact with neurons after peripheral nerve injury and contribute to persistent and intense pain sensation remains largely elusive. Our recent studies have shown that monocytes and microglia synergistically promote the development of neuropathic pain symptoms. We have also developed novel approaches for imaging and manipulating neurons and nonneuronal cells (e.g. monocytes, microglia and astrocytes) in the pain pathway, from peripheral dorsal root ganglia (DRG), the primary somatosensory cortex (S1) to anterior cingulate cortex (ACC) in the awake, behaving mice. In our preliminary studies, we have found that following peripheral nerve injury, DRG sensory neuron activities undergo rapid and transient increases whereas pyramidal neuronal activities in the S1 and ACC rise progressively and remain elevated under chronic pain states. Moreover, selective depletion of microglial cytokine TNF-alpha production attenuates pain hypersensitivity after nerve injury. Based on these findings, we hypothesize that the interactions among peripheral monocytes, brain microglia and astrocytes play critical roles in the emergence of hyperactive neurons in the cortex during the transition from acute to chronic pain. In this application, we will test this hypothesis by combining in vivo two-photon imaging of synapse structure and neuronal activity, genetic manipulation of molecularly defined cell types in cortical circuitry, as well as behavioral testing for sensory and affective pain symptoms. Specifically, in Aim 1, we will characterize the sequential changes of neuronal activities in the pain circuits after peripheral nerve injury. This will test the hypothesis that dynamic changes in pain circuits occur progressively from the DRG to the cortex and that persistent neuronal hyperactivity emerging in S1 and ACC is critical for the induction of chronic neuropathic pain. In Aim 2, we will combine in vivo calcium imaging with in vivo cell depletion and bone marrow chimeric strategies to investigate the synergistic roles of monocytes and microglia in the emergence of persistent cortical hyperactivity. In Aim 3, we will test the hypothesis that monocytes/microglia promote nerve injury- induced neuronal hyperactivity via proinflammatory cytokines and astrocytes in the cortex. Together, our proposed research will significantly expand the knowledge on the contribution of neuroimmune interactions to the development of neuropathic pain. They will also help identify immune cells as novel targets for the development of effective pain therapies.

项目总结/摘要 神经损伤引起的神经病理性疼痛是一个主要的健康问题，治疗有限。不足 在神经回路水平上对这种疾病的理解阻碍了有效疗法的发展。 已知免疫系统的激活和躯体感觉通路中的神经元改变是与免疫系统的激活和躯体感觉通路中的神经元改变相关的。 对神经性疼痛的发生至关重要。然而，免疫细胞如何与周围神经元相互作用， 神经损伤并导致持续和强烈的疼痛感觉仍然很难理解。我们最近的研究 已经表明单核细胞和小胶质细胞协同促进神经性疼痛的发展 症状我们还开发了成像和操纵神经元和非神经元的新方法。 疼痛通路中的细胞（例如单核细胞、小胶质细胞和星形胶质细胞），来自外周背根神经节（DRG）， 在清醒的行为小鼠中，初级躯体感觉皮层（S1）到前扣带皮层（ACC）。在我们 初步研究发现，周围神经损伤后，DRG感觉神经元活动 经历快速和短暂的增加，而在S1和ACC锥体神经元活动上升 在慢性疼痛状态下逐渐升高并保持升高。此外，选择性去除小胶质细胞 细胞因子TNF-α的产生减弱了神经损伤后的疼痛超敏反应。基于这些发现，我们 假设外周血单核细胞、脑小胶质细胞和星形胶质细胞之间的相互作用起关键作用 在从急性疼痛到慢性疼痛的过渡过程中，皮层神经元过度活跃。在这 应用，我们将测试这一假设结合在体内双光子成像的突触结构， 神经元活动，皮质回路中分子定义的细胞类型的遗传操作，以及 感觉和情感疼痛症状的行为测试。具体而言，在目标1中，我们将描述 周围神经损伤后痛回路神经元活动的时序性变化。这将考验 假设疼痛回路的动态变化从DRG到皮层逐渐发生， S1和ACC中出现的持续性神经元过度活动对于诱导慢性神经病理性 痛苦在目标2中，我们将联合收割机体内钙成像与体内细胞去除和骨髓嵌合相结合， 研究单核细胞和小胶质细胞在持续性脑缺血中的协同作用的策略 皮质机能亢进在目标3中，我们将检验单核细胞/小胶质细胞促进神经损伤的假设- 通过促炎细胞因子和皮质中的星形胶质细胞诱导神经元过度活跃。我们一起， 拟议的研究将大大扩展有关神经免疫相互作用对 神经性疼痛的发展。它们还将有助于识别免疫细胞作为免疫治疗的新靶点。 开发有效的疼痛疗法。

项目成果

A mesocortical glutamatergic pathway modulates neuropathic pain independent of dopamine co-release.

• DOI: 10.1038/s41467-024-45035-2
• 发表时间: 2024-01-20
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Li, Miao;Yang, Guang
• 通讯作者: Yang, Guang

Activation of VIP interneurons in the prefrontal cortex ameliorates neuropathic pain aversiveness.

• DOI: 10.1016/j.celrep.2022.111333
• 发表时间: 2022-09-13
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Li, Miao;Zhou, Hang;Teng, Sasa;Yang, Guang
• 通讯作者: Yang, Guang

Synchronized activity of sensory neurons initiates cortical synchrony in a model of neuropathic pain.

• DOI: 10.1038/s41467-023-36093-z
• 发表时间: 2023-02-08
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Chen, Chao;Sun, Linlin;Adler, Avital;Zhou, Hang;Zhang, Licheng;Zhang, Lihai;Deng, Junhao;Bai, Yang;Zhang, Jinhui;Yang, Guang;Gan, Wen-Biao;Tang, Peifu
• 通讯作者: Tang, Peifu

A sleep-active basalocortical pathway crucial for generation and maintenance of chronic pain.

睡眠活跃的基底层途径对于慢性疼痛的产生和维持至关重要。

• DOI: 10.1038/s41593-022-01250-y
• 发表时间: 2023-03
• 期刊: NATURE NEUROSCIENCE
• 影响因子: 25
• 作者: Zhou, Hang;Li, Miao;Zhao, Ruohe;Sun, Linlin;Yang, Guang
• 通讯作者: Yang, Guang