Nociceptive Mechanisms In Whiplash Injury

颈部扭伤的伤害感受机制

• 批准号: 7990109
• 负责人: Beth A Winkelstein
• 金额: $ 15.74万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990109
• 关键词: Address; Afferent Neurons; Animal Model; Applied Research; Area; Arthralgia; Back Pain; Behavioral; Biological Assay; Biomechanics; Brain; Bupivacaine; Cervical; Characteristics; Chronic; Clinical; Clinical Management; Clinical Research; Clinical Treatment; Clinical assessments; Collaborations; Complement; Complex; Control Groups; Data; Development; Diagnosis; Disease; Electrophysiology (science); Engineering; Facet joint structure; Fiber; Frequencies; Future; Glutamates; Goals; Healed; Immune; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Interdisciplinary Study; Intervention; Investigation; Joints; Lead; Low Back Pain; Maintenance; Maps; Measurement; Measures; Mediating; Methods; Modeling; Modification; Molecular; Musculoskeletal Diseases; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Neck; Nerve Fibers; Neuraxis; Neuroglia; Neuronal Plasticity; Neurons; Neuropeptides; Nociception; Operative Surgical Procedures; Orthopedics; Pain; Pain management; Pathway interactions; Patients; Pattern; Perception; Peripheral; Persistent pain; Placebos; Population; Public Health; Rattus; Relative (related person); Research; Research Activity; Research Personnel; Research Proposals; Rodent; Role; Schools; Sensory; Signal Transduction; Sodium Channel Blockers; Somatosensory Cortex; Spinal; Spinal Cord; Spinal Ganglia; Spinal Injuries; Spinal cord posterior horn; Stimulus; Symptoms; Syndrome; Techniques; Testing; Thalamic structure; Tissues; Toxin; Translating; Ventral Posterolateral Nucleus; Vertebral column; Veterinarians; Veterinary Medicine; Whiplash Injuries; Work; capsule; chronic pain; computerized data processing; defined contribution; design; dorsal horn; effective therapy; extracellular; healing; immune activation; improved; injured; innovation; insight; interdisciplinary collaboration; interest; joint injury; mechanical allodynia; musculoskeletal injury; neuroinflammation; neurotrophic factor; nociceptive response; novel; parent grant; public health relevance; receptive field; relating to nervous system; research study; response; skills; soft tissue; treatment strategy; voltage

DESCRIPTION (provided by applicant): In this BIRT application, we establish a new collaboration to substantially expand ongoing activities under the Parent Grant to define the mechanistic relationships between neuronal plasticity and spinal immune activation in chronic pain in the spine. In particular, this application addresses the spinal disorder of facet joint injury-mediated chronic pain, which is a soft tissue and joint injury in the spine that can lead to chronic neck and low back pain, encompassing a major musculoskeletal disorder, with far-reaching clinical implications. The proposed research represents a new interdisciplinary collaboration between an engineer (PI, Dr. Winkelstein) in the School of Engineering and Applied Sciences, who has expertise in injury biomechanics and development of painful injury models in the rodent, and a clinician (Dr. Golder) in the School of Veterinary Medicine who has both clinical and research expertise in neural electrophysiological recording techniques and clinical assessment and management of pain in veterinary species. This collaboration represents a first step in building a new interdisciplinary research team through a new formal collaboration to study spinal neuron activity in response to painful injury. Our proposal combines two complementary researchers who have not worked together formally in any way but have the necessary scientific backgrounds and skills to enable making a major contribution to the area of orthopaedic pain, and its diagnosis and treatment. In addition, the proposed activities are far-removed from the primary research activities underway in either lab so they are not possible without such an integrative approach. A significant challenge exists in treating painful musculoskeletal disorders owing to the research challenges that exist in simultaneously investigating the neuronal and immune contributions that drive the development and maintenance of chronic pain. This challenge is due in part to the fact that truly interdisciplinary teams, with the appropriate expertise and specialization, are needed to attack this problem. The Parent Grant focuses on defining the relationships between biomechanics of tissue injury and the inflammatory contributions to the resulting pain responses. Proposed supplemental studies in this application expand those investigations via aims that utilize elextrophysiological techniques to map the spatial and temporal responses of nociceptive spinal neurons to identify the mechanisms responsible for the development of chronic pain after spinal injury. We also expand the scope of studies in the Parent Grant by assessing glutamate activity in neuronal and glial cells in the thalamus, where pain signals are amplified and translated to the somatosensory cortex of the brain. Both of these scientific approaches are a direct result of a new collaboration for the PI with a neuroscientist and veterinarian. Our innovative research proposal leverages several separate fields to develop an integrated understanding of the complex problem of pain. The proposed experiments are designed to overcome difficult technical and analytical challenges and to provide integrated mechanisms leading to chronic pain in order to help inform clinical treatment strategies. Accordingly, we propose three novel interdisciplinary specific aims to expand the Parent Grant activities through a new collaboration: Aim 1. Measure extracellular voltage recordings of sensory neurons in the dorsal horn of the spinal cord at day 1 and day 14 following whiplash injuries that produces persistent pain. Aim 2. Define the relative contributions of afferent fiber types in the facet joint to the development of spinal cord neuronal plasticity following whiplash injury, using toxins to selectively ablate nerve fibers and measuring extracellular voltage recordings in the spinal cord. Aim 3. Quantify pain symptoms and extracellular voltage recordings of spinal neurons after whiplash injury followed by injection of the sodium channel blocker, bupivacaine, to block sensory fiber activity from the injured joint. Neuronal responses will be measured after injection to define the contributions of sensory inputs from the joint to the maintenance of chronic pain. This interdisciplinary collaboration will begin to characterize the integrated relationships between neuronal- inflammatory cascades in the CNS that lead to whiplash pain. Our research team is uniquely-suited to address the challenges with implementing the required techniques to test our hypothesis, owing to our collective expertise in engineering and injury biomechanics (Winkelstein), electrophysiology (Golder), animal modeling and pain (Winkelstein & Golder). Activities proposed in this BIRT application are substantively different from aims in the Parent Grant and are highly relevant to research areas in NIAMS. The aims of the Parent Grant focus on defining the glial cell activation and neurotrophin responses in the dorsal root ganglia and spinal cord, and defining local inflammatory responses in the facet joint for whiplash pain. However, that proposal does not address neuronal responses explicitly. We have a recent interest in expanding assessment of cellular responses to include the brain, where pain signals are processed and perceived. Certainly, through the establishment of these interdisciplinary research activities, our ongoing efforts to understand whiplash pain will be greatly expanded in directions beyond the scope of the Parent Grant. Indeed, the investigators will continue to collaborate after the period of the BIRT and will develop future proposals focused on developing targeted pharmacologic treatments for joint pain, clinical interventions for back pain and methods for improved tissue healing. PUBLIC HEALTH RELEVANCE: Chronic pain is a significant public health problem and continues to present a variety of challenges in its clinical management. Among current obstacles is an inadequate ability to effectively treat patients with pain from musculoskeletal injuries because the mechanisms of chronic pain in these syndromes are not well-defined. This research proposal will define neuronal firing patterns in the spinal cord and patterns of cellular pain responses in the brain after whiplash-mediated joint injury in the spine, a common injury in the neck. The overall goal of this work is to identify characteristic temporal neuronal profiles involved in the development of chronic pain. Findings from these studies have the potential to identify and enable development of effective treatments and clinical management approaches for this chronic pain syndrome, as well as for facet joint- mediated low back pain.

描述（由申请人提供）：在这个BIRT申请中，我们建立了一个新的合作，以实质性地扩大在父母资助下正在进行的活动，以定义脊柱慢性疼痛中神经元可塑性和脊髓免疫激活之间的机制关系。特别地，本应用程序解决了小关节损伤介导的慢性疼痛的脊柱疾病，这是一种脊柱软组织和关节损伤，可导致慢性颈部和腰痛，包括主要的肌肉骨骼疾病，具有深远的临床意义。拟议的研究代表了工程与应用科学学院的工程师（PI, Dr. Winkelstein）和兽医学院的临床医生（Dr. Golder）之间新的跨学科合作，前者在损伤生物力学和啮齿动物疼痛损伤模型的开发方面具有专业知识，后者在神经电生理记录技术和兽医物种疼痛的临床评估和管理方面具有临床和研究专业知识。这项合作代表了通过新的正式合作建立一个新的跨学科研究团队的第一步，以研究脊髓神经元对疼痛损伤的反应。我们的提议结合了两位互补的研究人员，他们没有以任何方式正式合作，但具有必要的科学背景和技能，能够为骨科疼痛及其诊断和治疗领域做出重大贡献。此外，拟议的活动与两个实验室正在进行的主要研究活动相去甚远，因此如果没有这种综合方法，它们是不可能的。由于同时研究驱动慢性疼痛发展和维持的神经元和免疫贡献，因此在治疗疼痛性肌肉骨骼疾病方面存在重大挑战。这一挑战部分是由于需要真正的跨学科团队，具有适当的专业知识和专业化，来解决这个问题。父母资助的重点是定义组织损伤的生物力学和炎症对疼痛反应的影响之间的关系。本研究中提出的补充研究扩展了这些研究，目的是利用外生理学技术来绘制伤害性脊髓神经元的空间和时间反应，以确定脊髓损伤后慢性疼痛发展的机制。我们还通过评估丘脑中神经元和神经胶质细胞中的谷氨酸活性来扩大父母赠款的研究范围，其中疼痛信号被放大并翻译到大脑的体感皮层。这两种科学方法都是PI与神经科学家和兽医新合作的直接结果。我们的创新研究计划利用几个独立的领域来发展对疼痛复杂问题的综合理解。提出的实验旨在克服困难的技术和分析挑战，并提供导致慢性疼痛的综合机制，以帮助告知临床治疗策略。因此，我们提出三个新的跨学科的具体目标，通过新的合作来扩大父母奖助金活动：目标1。测量脊髓背角感觉神经元的细胞外电压记录，在第1天和第14天鞭打损伤后产生持续疼痛。目标2。使用毒素选择性地切除神经纤维并测量脊髓的细胞外电压记录，确定小关节内传入纤维类型对鞭打损伤后脊髓神经元可塑性发展的相对贡献。目标3。量化鞭打损伤后脊髓神经元的疼痛症状和细胞外电压记录，随后注射钠通道阻滞剂布比卡因，以阻断受伤关节的感觉纤维活动。注射后将测量神经元反应，以确定来自关节的感觉输入对维持慢性疼痛的贡献。这一跨学科的合作将开始表征中枢神经系统中导致鞭打痛的神经元炎症级联之间的综合关系。由于我们在工程和损伤生物力学（Winkelstein），电生理学（Golder），动物建模和疼痛（Winkelstein & Golder）方面的集体专业知识，我们的研究团队非常适合解决实施所需技术以测试我们的假设的挑战。本BIRT申请中提出的活动与父母资助的目标有本质上的不同，并且与NIAMS的研究领域高度相关。本研究的目的是确定背根神经节和脊髓的神经胶质细胞活化和神经营养反应，并确定小关节局部炎症反应。然而，这一建议并没有明确地解决神经元的反应。我们最近对扩大细胞反应的评估感兴趣，将大脑也包括在内，大脑是处理和感知疼痛信号的地方。当然，通过建立这些跨学科的研究活动，我们正在进行的理解鞭打痛的努力将大大扩展到父母资助范围之外的方向。事实上，在BIRT结束后，研究人员将继续合作，并将制定未来的建议，重点是开发针对关节疼痛的靶向药物治疗，背部疼痛的临床干预和改善组织愈合的方法。