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

描述（由申请人提供）：外周神经性疼痛是由中枢神经系统的适应不良变化引起的，这些变化是由受损感觉神经元的异常活动引发的。越来越多的证据表明，脊髓的神经可塑性依赖于胶质细胞-神经元的相互作用。在神经病理性疼痛中，胶质细胞在超敏反应的发展和维持中起关键作用。我们的数据表明，神经肽前体蛋白VGF（非首字母缩写）和它衍生的肽可能代表新的损伤诱导的神经胶质激活剂。我们已经表明，1）在神经损伤开始时，VGF在感觉神经元中快速且稳健地上调，以及2）VEGF衍生的肽激活脊髓小胶质细胞。VGF肽还引起热痛觉过敏、机械和冷异常性疼痛，并增强背角神经元的活性。这些结果强烈暗示VGF肽作为感觉神经元信号，在神经损伤后启动小胶质细胞活化并参与脊髓神经可塑性。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起始和维持。我们的长期研究目标是阐明VEGF源性神经肽在慢性疼痛中的作用。本申请的目的是确定VGF肽如何驱动导致神经性疼痛的脊髓神经可塑性，并确定它们是否是维持神经性疼痛所必需的。该建议的中心假设是VGF肽作为从急性疼痛向慢性疼痛转变的关键介质。在具体目标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肽是小胶质细胞活化和神经损伤诱导的超敏反应的发展所必需的，并且VGF消融或VGF肽的免疫中和将防止这些事件。在具体目标2中，我们将确定VGF对维持神经病理性疼痛状态的贡献。我们假设，在神经性疼痛的持续时间内，脊髓和CSF中VGF肽的水平和/或加工发生改变，并且神经性疼痛将通过VGF消融而消除。在具体目标3中，我们将描述负责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适应不良神经可塑性。生物活性的VGF衍生肽的表征，其可以另外建立神经病理状态的新的CSF生物标志物、VGF信号传导系统和介导VGF作用的肽受体，具有鉴定控制脊髓神经可塑性的新的治疗方法的潜力，提供对神经病理性疼痛的发展和进展的洞察。

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.