VGF, critical role in the transition from acute to chronic pain

VGF，在急性疼痛向慢性疼痛转变中的关键作用

• 批准号: 8152905
• 负责人: STEPHEN R SALTON
• 金额: $ 52.4万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8152905
• 关键词: Ablation; Acute; Afferent Neurons; Animal Model; Behavioral; Biological Markers; Brain; Cerebrospinal Fluid; Chickenpox; Data; Development; Diagnosis; Drug Delivery Systems; Event; Genes; Goals; Herpes zoster disease; Hypersensitivity; Infection; Injury; Lead; Maintenance; Mechanics; Mediating; Mediator of activation protein; Messenger RNA; Meta-Analysis; Microglia; Modeling; Molecular; Neuraxis; Neuroglia; Neuronal Plasticity; Neurons; Neuropathy; Neuropeptides; Pain; Peptide Receptor; Peptides; Perception; Peripheral; Play; Posterior Horn Cells; Prevention; Process; Protein Precursors; Proteins; Regulation; Research; Role; Signal Transduction; Spinal; Spinal Cord; System; Therapeutic; Thermal Hyperalgesias; Traumatic Nerve Injury; Up-Regulation; VGF protein; allodynia; chemokine; chronic neuropathic pain; chronic pain; expectation; improved; injured; insight; nerve injury; novel; novel strategies; novel therapeutic intervention; painful neuropathy; prevent; receptor

DESCRIPTION (provided by applicant): Peripheral neuropathic pain results from maladaptive changes in the central nervous system that are initiated by abnormal activity of injured sensory neurons. Increasing evidence indicates that neuroplasticity in the spinal cord depends on glial-neuronal interactions. In neuropathic pain, glial cells play a critical role in both the development and maintenance of hypersensitivity. Our data suggest that the neuropeptide precursor protein VGF (non-acronymic) and the peptides derived from it may represent novel injury-induced glial activators. We have shown that 1) VGF is rapidly and robustly upregulated in sensory neurons at the onset of nerve injury, and 2) VGF-derived peptides activate spinal microglia. VGF peptides also evoke thermal hyperalgesia, and mechanical and cold allodynia, and potentiate the activity of dorsal horn neurons. These results strongly implicate VGF peptides as sensory neuron signals that initiate microglial activation after nerve injury and participate in spinal neuroplasticity. Furthermore, VGF remains upregulated for the duration of the behavioral hypersensitivity, indicating that VGF peptides may participate both in the initiation of neuropathic pain and also in its maintenance. Our long-term research goal is to delineate the role that VGF-derived neuropeptides play in conditions of chronic pain. Our objective in this application is to determine how VGF peptides drive the spinal neuroplasticity that leads to neuropathic pain, and to establish whether they are required for its maintenance. The central hypothesis of this proposal is that VGF peptides serve as key mediators of the transition from acute to chronic pain. In Specific Aim 1, we will determine the role of VGF peptides in the spinal neuroplasticity that leads to neuropathic pain. We hypothesize that VGF peptides are required for microglial activation and the development of nerve injury-induced hypersensitivity, and that VGF ablation or immunoneutralization of VGF peptides will prevent these events. In Specific Aim 2, we will determine the contribution of VGF to the maintenance of the neuropathic pain state. We hypothesize that the levels and/or processing of VGF peptides in spinal cord and CSF are altered for the duration of neuropathic pain and that neuropathic pain will be abolished by VGF ablation. In Specific Aim 3, we will delineate the mechanisms responsible for VGF regulation of spinal neuroplasticity. We hypothesize that VGF peptides regulate the neuromodulatory activity of microglia that drives maladaptive neuroplasticity in dorsal horn neurons. Characterization of biologically active VGF-derived peptides, which may additionally establish novel CSF biomarkers of the neuropathic state, the VGF signaling system, and the peptide receptors that mediate VGF actions, has the potential to identify new therapeutic approaches to control spinal neuroplasticity, providing insight into the development and progression of neuropathic pain. PUBLIC HEALTH RELEVANCE: Increased effort to understand what causes pain has motivated a multi-decade global research effort to identify new molecular players that communicate the perception of pain to the brain. The proposed research will investigate the activity of a novel spinal pain signaling system, that of the neuropeptide precursor protein VGF (non-acronymic). We have recently shown that under conditions of chronic pain, this protein increases in sensory neurons. We hypothesize that this protein contributes to injury signals that mediate the development of chronic pain. Understanding how VGF drives pain signaling may lead to new approaches for diagnosing and treating chronic pain conditions.

描述（由申请人提供）：周围神经性疼痛是由受损感觉神经元异常活动引发的中枢神经系统的不适应变化引起的。越来越多的证据表明，脊髓的神经可塑性取决于神经胶质-神经元的相互作用。在神经性疼痛中，神经胶质细胞在超敏反应的发展和维持中起着关键作用。我们的数据表明，神经肽前体蛋白VGF（非首字母缩略词）及其衍生的肽可能代表新的损伤诱导的神经胶质激活剂。我们已经证明1)VGF在神经损伤开始时在感觉神经元中迅速而强烈地上调，2)VGF衍生的肽激活脊髓小胶质细胞。VGF肽还能引起热痛觉过敏、机械和冷异常性疼痛，并增强背角神经元的活动。这些结果强烈暗示VGF肽作为神经损伤后启动小胶质细胞激活和参与脊髓神经可塑性的感觉神经元信号。此外，VGF在行为超敏反应的持续时间内保持上调，表明VGF肽可能参与神经性疼痛的开始和维持。我们的长期研究目标是描述vgf衍生神经肽在慢性疼痛条件下的作用。我们的目的是确定VGF肽如何驱动导致神经性疼痛的脊髓神经可塑性，并确定其维持是否需要它们。该建议的中心假设是VGF肽作为从急性到慢性疼痛过渡的关键介质。在特异性目标1中，我们将确定VGF肽在导致神经性疼痛的脊髓神经可塑性中的作用。我们假设VGF肽是小胶质细胞激活和神经损伤引起的超敏反应的必要条件，而VGF消融或VGF肽的免疫中和将阻止这些事件的发生。在特异性目标2中，我们将确定VGF对神经性疼痛状态维持的贡献。我们假设脊髓和脑脊液中VGF肽的水平和/或加工在神经性疼痛期间发生改变，而神经性疼痛将通过VGF消融而消除。在Specific Aim 3中，我们将描述VGF调节脊髓神经可塑性的机制。我们假设VGF肽调节小胶质细胞的神经调节活性，从而驱动背角神经元的神经可塑性不良。表征具有生物活性的VGF衍生肽，可能会建立新的脑脊液生物标志物，神经病变状态，VGF信号系统，以及介导VGF作用的肽受体，有可能确定新的治疗方法来控制脊髓神经可塑性，为神经性疼痛的发生和进展提供见解。