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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

基本信息

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
项目类别：
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

项目摘要

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/文摘

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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。