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: 8518292
• 负责人: STEPHEN R SALTON
• 金额: $ 50.37万
• 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/8518292
• 关键词: Ablation; Acute; Afferent Neurons; Animal Model; Behavioral; Biological Markers; Brain; Cerebrospinal Fluid; Chickenpox; Data; Development; Diagnosis; Drug Targeting; 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.

描述(申请人提供)：周围神经病理性疼痛是由受损感觉神经元的异常活动引起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，脊髓的神经可塑性依赖于神经胶质-神经元的相互作用。在神经病理性疼痛中，神经胶质细胞在超敏反应的发生和维持中起着关键作用。我们的数据提示，神经肽前体蛋白VGF(非首字母缩写)及其衍生的多肽可能是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，以及2)VGF衍生的多肽激活脊髓小胶质细胞。VGF多肽还可引起热痛觉过敏、机械性和冷痛觉过敏，并增强背角神经元的活动。这些结果有力地表明，VGF多肽是感觉神经元信号，在神经损伤后启动小胶质细胞的激活，并参与脊髓神经可塑性。此外，VGF在行为过敏的持续时间内持续上调，这表明VGF多肽可能参与了神经病理性疼痛的启动和维持。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所起的作用。我们在这项应用中的目标是确定VGF多肽如何驱动导致神经病理性疼痛的脊髓神经可塑性，并确定它们是否是维持脊髓可塑性所必需的。这一建议的中心假设是，VGF多肽是从急性疼痛向慢性疼痛过渡的关键介质。在具体目标1中，我们将确定VGF多肽在导致神经病理性疼痛的脊髓神经可塑性中的作用。我们假设VGF多肽是小胶质细胞激活和神经损伤诱导的超敏反应发展所必需的，VGF消融或免疫中和将阻止这些事件的发生。在具体目标2中，我们将确定VGF在维持神经病理性疼痛状态中的作用。我们假设在神经病理性疼痛的持续时间内，脊髓和脑脊液中的VGF多肽的水平和/或处理会发生改变，VGF消融将消除神经病理性疼痛。在具体目标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多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适应性神经可塑性。对具有生物活性的VGF衍生肽的表征，可能会额外建立神经病变状态的新的脑脊液生物标记物、VGF信号系统以及介导VGF作用的多肽受体，有可能发现控制脊髓神经可塑性的新的治疗方法，从而深入了解神经病理性疼痛的发展和进展。