Descending Modulation of Nerve Injury and Injury-Evoked Pain

神经损伤和损伤引起的疼痛的降序调节

• 批准号: 8336485
• 负责人: Toni Shippenberg
• 金额: $ 78.27万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8336485
• 关键词: AMPA Receptors; Acquired Immunodeficiency Syndrome; Affect; Affective; Age Distribution; American; Analgesics; Animal Model; Animals; Anterior; Area; Attenuated; Behavior; Behavioral; Biochemical; Brain; Brain region; Coupling; Data; Development; Disease; Etiology; Exhibits; Family; Fibromyalgia; Functional Imaging; Gene Deletion; Goals; HIV; Healed; Highly Active Antiretroviral Therapy; Human; Hyperalgesia; Hypersensitivity; Image; Indium; Individual; Individual Differences; Inferior; Inflammation; Injury; Investigation; Knockout Mice; Lentivirus Vector; Lesion; Limb structure; Lobule; Longitudinal Studies; Magnetic Resonance Imaging; Maintenance; Measures; Mechanics; Medial; Mediating; Metabolism; Modeling; Nature; Nerve Degeneration; Nervous system structure; Neurons; Neuropathy; Neurosciences; Nociception; Nociceptive Stimulus; Opiates; Output; PTX3 protein; Pain; Pain management; Parietal; Pathogenesis; Patients; Peripheral; Peripheral nerve injury; Persistent pain; Phantom Limb Pain; Pharmaceutical Preparations; Physicians; Posterior Horn Cells; Prefrontal Cortex; Primary Hyperalgesias; Process; Protein Family; Proteins; Public Health; Rattus; Receptor Activation; Recording of previous events; Research; Rest; Risk; Role; Secondary Hyperalgesias; Sensory; Societies; Spinal; Spinal Cord; Stimulus; Structure; Symptoms; Synapses; Synaptic Transmission; Syndrome; System; Techniques; Testing; Thalamic structure; Therapeutic; Time; Tissues; Viral; addiction; allodynia; antiretroviral therapy; base; chronic back pain; chronic neuropathic pain; chronic pain; cohort; cost; density; diabetes mellitus therapy; effective therapy; experience; gray matter; healing; illness length; inflammatory neuropathic pain; inflammatory pain; injured; member; nerve injury; neuroimaging; neuronal pentraxin; novel; novel therapeutics; opioid abuse; pain behavior; painful neuropathy; preclinical study; prescription opiate; prevent; receptor function; repaired; response; somatosensory; spontaneous pain; therapy development; tool; translational study; transmission process; white matter

Neuroimaging techniques have provided effective tools for investigating the influence of pain on CNS function. Human imaging studies have identified a pain matrix composed of brain regions that are activated by nociceptive stimuli. Activation is observed in the secondary somatosensory and insular regions, the anterior cingulate as well as the primary somatosensory area and thalamus. More limited evidence indicates decreased activity in a network that includes the inferior parietal lobule, and the medial prefrontal cortex. These regions are thought to subserve discriminative sensory pain transmission and to process affective-motivational components of pain. MRI investigations in chronic neuropathic pain indicate brain neurodegeneration and decreased gray matter volume and density in patients with chronic back pain, phantom pain, or fibromyalgia, although degree and regional distribution varies. Chronic back pain patients show activation of the prefrontal cortex during spontaneous pain, the same area that shows a reduction in gray matter density, as well as disruption in resting functional connectivity of widespread cortical areas. The nature of structural changes remains to be determined, whether neurodegeneration is causal and if analgesics prevent these changes. A difficulty in human research is assembling a homogenous patient cohort with matched symptoms, disease duration, medication history and age distribution. Since subjects are not tested prior to pain onset, individual differences that may predispose pain vulnerability can not be assessed. Importantly, the response to nerve injury and to different treatments varies among patients with comparable pain syndromes and not all patients exhibit neuropathic pain behavior after a demonstrable nerve injury. For these reasons, human functional imaging has not yet provided reproducible findings specific to the disease or a pathophysiological basis for symptomology. Prior to the advent of small animal imaging, preclinical studies could not directly measure spontaneous pain, a limitation in their utility as models of neuropathic pain. However, procedural advances now allow quantification of alterations in resting state connectivity and stimulus-evoked activity. The coupling of imaging to animal models of neuropathic pain allows longitudinal study of the development of pain and its expression. Changes in brain function that occur during spontaneous and stimulus-evoked pain can be assessed as a function of pain duration: grey matter volume and white matter integrity can be assessed over time. Using MRI and MRS techniques and the spared nerve injury (SNI) model of neuropathic pain in rats, ongoing studies seek to: i) identify changes in brain structure, function and metabolism that occur in the pain matrix as a function of the duration of neuropathic pain; ii) determine whether individuals differ in vulnerability to SNI-evoked pain and whether these differences are associated with differences in brain function and iii) determine whether a manipulation that we have shown to prevent the development of or reverse the expression of SNI-evoked allodynia and hyperalgesia (see below) reduces SNI-evoked alterations in spontaneous and evoked brain activity, functional connectivity, concentrations of biochemical compounds, grey matter volume and white matter integrity. Using advanced MRI and MRS techniques developed within the IRP, we expect to identify maladaptive brain plasticity at a systems level in the SNI rats, and to correlate brain plasticity with behavioral pain measures. The proposed translational studies will enable identification of a disease-modifying strategy aimed at both preventing maladaptive plasticity and identifying intrinsic risk individuals The rostral ventromedial medulla (RVM) constitutes the efferent component of pain-control systems that descend from the brain to the spinal cord. Considerable evidence has emerged regarding participation of this system in persistent pain conditions such as inflammation and neuropathy. The RVM normally exerts an inhibitory influence on dorsal horn neurons However, persistent noxious stimulation triggers time-related alterations in RVM synaptic activity. In inflammatory pain models, descending facilitation transiently increases reducing the net effect of inhibition. Over time, descending inhibition increases resulting in decreased nocifensive behavior. After nerve injury, RVM plasticity leads to facilitation of spinal cord nociceptive output, exacerbation of primary hyperalgesia and enhanced sensory input from adjacent regions (secondary hyperalgesia). AMPA receptor activation in the RVM has been shown to inhibit spinal nociceptive transmission and nocifensive behavior. Increased AMPA receptor function in the RVM is implicated in the activity-dependent plasticity that occurs in response to persistent pain produced by tissue inflammation. Targeting and synaptic clustering of AMPA receptors is essential for efficient excitatory transmission. Neuronal pentraxin 1 (NP1) is a member of the pentraxin family of proteins that is expressed exclusively in neurons and facilitates AMPA receptor clustering. Given the postulated role of NP1 in excitatory synaptic transmission and AMPA receptor systems in pain processing, we have used gene deletion and viral-mediated transfer techniques to examine whether manipulations that target this protein can affect the expression of persistent pain. To determine the contribution of NP1 to nerve-injury evoked pain, we assessed mechanical hypersensitivity in wild type and NP1 knock out mice following spared nerve injury. Nerve injury led to marked mechanical hypersensitivity of the injured limb. This enhanced nociception is significantly inhibited in NP1 knockout mice. In order to probe the specific involvement of RVM NP1 in mediating the attenuated response of NP1 knockout mice, we infused a lentiviral vector which drives expression of functional NP1 protein directly into the RVM. Selective rescue of RVM NP1 expression in knockout mice restores allodynia produced by nerve injury. Consistent with the data obtained in NP1 knockout mice, silencing NP1 expression in the RVM of rats prior to nerve injury inhibits allodynia. Furthermore, it decreases mechanical hyperalgesia. These findings are consistent with the observation that descending facilitatory systems arising in the RVM are necessary for the maintenance of neuropathic pain and identify NP1 in the RVM as a critical element in the descending facilitation of nerve-injury evoked pain. Together, these data suggest that targeting NP1 may be a novel therapeutic strategy for reversing persistent pain of diverse etiologies. On-going studies examining the role of NP1 in other conditions including those associated with AIDS antiretroviral therapy and peripheral inflammation indicate a key role of this protein in the development of persistent pain. Preliminary studies examining the contribution of another pentraxin, pentraxin 3 suggest a global role of the pentraxin family of proteins in the pathogenesis of nerve injury, neuropathic and inflammatory pain.

神经影像技术为研究疼痛对中枢神经系统功能的影响提供了有效的工具。 人类成像研究已经确定了由伤害性刺激激活的大脑区域组成的疼痛矩阵。在次级体感和岛区、前扣带回以及初级体感区和丘脑中观察到激活。 更有限的证据表明，包括顶下小叶和内侧前额叶皮层在内的网络活动减少。这些区域被认为有助于区分性感觉疼痛的传递并处理疼痛的情感动机成分。 慢性神经病理性疼痛的 MRI 检查表明，慢性背痛、幻痛或纤维肌痛患者存在脑神经变性以及灰质体积和密度下降，尽管程度和区域分布各不相同。慢性背痛患者在自发性疼痛期间表现出前额皮质的激活，该区域的灰质密度降低，并且广泛皮质区域的静息功能连接受到破坏。结构变化的性质仍有待确定，神经退行性变是否是因果关系以及镇痛药是否可以阻止这些变化。 人类研究的一个困难是组装具有匹配症状、病程、用药史和年龄分布的同质患者队列。由于受试者在疼痛发作前没有接受测试，因此无法评估可能导致疼痛脆弱性的个体差异。重要的是，具有类似疼痛综合征的患者对神经损伤和不同治疗的反应各不相同，并且并非所有患者在明显的神经损伤后都表现出神经性疼痛行为。由于这些原因，人体功能成像尚未提供针对该疾病的可重复发现或症状学的病理生理学基础。在小动物成像出现之前，临床前研究无法直接测量自发性疼痛，这限制了它们作为神经性疼痛模型的实用性。 然而，程序的进步现在允许量化静息状态连接和刺激诱发活动的变化。将成像与神经性疼痛动物模型相结合，可以对疼痛的发展及其表达进行纵向研究。自发性疼痛和刺激引起的疼痛期间发生的脑功能变化可以作为疼痛持续时间的函数进行评估：可以随时间评估灰质体积和白质完整性。利用 MRI 和 MRS 技术以及大鼠神经性疼痛的幸存神经损伤 (SNI) 模型，正在进行的研究旨在： i) 确定疼痛基质中发生的大脑结构、功能和代谢的变化，作为神经性疼痛持续时间的函数。疼痛; ii) 确定个体对 SNI 诱发疼痛的脆弱性是否存在差异，以及这些差异是否与大脑功能的差异有关，以及 iii) 确定我们已经证明可以预防 SNI 诱发异常性疼痛的发展或逆转 SNI 诱发异常性疼痛表达的操作是否与痛觉过敏（见下文）可减少 SNI 诱发的自发和诱发大脑活动、功能连接、生化化合物浓度、灰质体积和白质完整性的改变。利用 IRP 开发的先进 MRI 和 MRS 技术，我们期望在 SNI 大鼠的系统水平上识别适应不良的大脑可塑性，并将大脑可塑性与行为疼痛测量相关联。拟议的转化研究将能够确定一种疾病缓解策略，旨在预防适应不良可塑性并识别内在风险个体 延髓头端腹内侧 (RVM) 构成从大脑下降到脊髓的疼痛控制系统的传出部分。大量证据表明该系统参与持续性疼痛病症，例如炎症和神经病变。 RVM 通常对背角神经元产生抑制作用，然而，持续的有害刺激会触发 RVM 突触活动的时间相关变化。 在炎性疼痛模型中，下降促进短暂增加，减少了抑制的净效应。 随着时间的推移，下降抑制增加，导致伤害行为减少。神经损伤后，RVM 可塑性导致脊髓伤害性输出的促进、原发性痛觉过敏的加剧以及邻近区域的感觉输入的增强（继发性痛觉过敏）。 RVM 中的 AMPA 受体激活已被证明可以抑制脊髓伤害性传递和伤害行为。 RVM 中 AMPA 受体功能的增强与活动依赖性可塑性有关，这种可塑性是对组织炎症产生的持续疼痛做出反应而发生的。 AMPA 受体的靶向和突触聚集对于有效的兴奋性传递至关重要。神经元五聚蛋白 1 (NP1) 是五聚蛋白家族的成员，仅在神经元中表达并促进 AMPA 受体聚集。 鉴于 NP1 在兴奋性突触传递中的假定作用以及 AMPA 受体系统在疼痛处理中的作用，我们使用基因删除和病毒介导的转移技术来检查针对该蛋白的操作是否会影响持续性疼痛的表达。为了确定 NP1 对神经损伤引起的疼痛的影响，我们评估了野生型和 NP1 敲除小鼠在神经损伤后的机械超敏反应。神经损伤导致受伤肢体明显的机械过敏。这种增强的伤害感受在 NP1 敲除小鼠中被显着抑制。为了探究 RVM NP1 在介导 NP1 敲除小鼠的减毒反应中的具体参与，我们将驱动功能性 NP1 蛋白直接表达的慢病毒载体注入 RVM。选择性挽救基因敲除小鼠中的 RVM NP1 表达可恢复神经损伤产生的异常性疼痛。与在 NP1 敲除小鼠中获得的数据一致，在神经损伤之前沉默大鼠 RVM 中的 NP1 表达可抑制异常性疼痛。此外，它还能减少机械性痛觉过敏。这些发现与以下观察结果一致：RVM 中出现的下降易化系统对于维持神经性疼痛是必要的，并且将 RVM 中的 NP1 确定为神经损伤诱发疼痛的下降易化的关键元素。总之，这些数据表明，靶向 NP1 可能是逆转不同病因引起的持续性疼痛的一种新的治疗策略。正在进行的研究检查 NP1 在其他疾病中的作用，包括与艾滋病抗逆转录病毒治疗和周围炎症相关的疾病，表明该蛋白质在持续性疼痛的发展中发挥着关键作用。 初步研究检查了另一种五聚蛋白五聚蛋白 3 的作用，表明五聚蛋白家族蛋白在神经损伤、神经性疼痛和炎性疼痛的发病机制中发挥着重要作用。