NEURAL AND CHEMICAL BASIS OF PATHOLOGIC PAIN

病理性疼痛的神经和化学基础

• 批准号: 7537162
• 负责人: Jun-Ming Zhang
• 金额: $ 34.13万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7537162
• 关键词: Abbreviations; Accounting; Acute; Affect; Afferent Neurons; Animal Model; Biological Assay; Brain; CCL2 gene; Cerebrospinal Fluid; Chemicals; Chronic; Clinical; Data; Development; Electrodes; Equilibrium; Fiber; Growth; HIV Infections; Herpes zoster disease; Hyperalgesia; Immune system; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-6; Interleukins; Ligation; Low Back Pain; Maintenance; Mechanics; Mediating; Membrane; Methods; Modeling; Monocyte Chemoattractant Proteins; Nerve; Neurons; Oncogenes; Pain; Pathologic; Perfusion; Peripheral Nerves; Peripheral nerve injury; Play; Property; Proteins; Radiculopathy; Rattus; Resistance; Role; Rupture; Screening procedure; Spinal Cord; Spinal Ganglia; Spinal nerve structure; System; TNF gene; Testing; Text; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Virus Diseases; Voltage-Clamp Technics; allodynia; base; behavior measurement; chemokine; chronic pain; cytokine; electrical property; improved; in vivo; insight; irritation; new therapeutic target; pain behavior; painful neuropathy; prevent; relating to nervous system; research study; voltage clamp

DESCRIPTION (provided by applicant): The proposed experiments will examine the role of inflammatory responses in the dorsal root ganglion (DRG) in the development and persistence of pathologic pain. Inflammatory responses have been observed in the DRG following various clinical conditions that are often associated with acute or chronic pain: lumbar disc herniation/rupture, mechanical compression, viral infection (e.g., shingles, HIV infection), and peripheral nerve injury. Most studies of inflammation in chronic pain have focused on spinal cord, brain, and peripheral nerve. However, it is not known how prolonged inflammation affects the functional or electrophysiological properties of the primary sensory neurons, how the cytokine profile changes in the DRG following inflammatory irritation, and which cytokines are most important in the initiation and persistence of pathological pain states. We have developed a new rat model of localized inflammation of the DRG. This model shows prolonged pain behaviors, spontaneous activity, and changes in a number of different cytokines that are similar to those induced by mechanical compression. The new model allows us to examine the effects of inflammation per se, in the absence of other types of nerve damage. We hypothesize that altered functional properties of the sensory neurons in the inflamed DRGs and the subsequent pathologic pain can be at least partially accounted for by altered activity of the hyperpolarization-activated current (HCN or IH), resulting from imbalanced cytokine expression within the DRG. Using both the mechanical compression and the DRG inflammation models, we will test our hypothesis via 3 Specific Aims (SA). SA1: Identify significantly altered cytokines/chemokines in the locally inflamed DRGs. SA2. Assess changes in the electrophysiological properties of DRG neurons after direct and prolonged inflammatory irritation, and determine if the IH plays an important role in increased excitability and spontaneous activity. SA3. Manipulate the levels of key cytokines (identified in SA1) in vivo to determine their contribution to pain behaviors and the underlying changes in neuronal electrical properties. Using our previously developed methods for long term in vivo perfusion of DRG, we will study the effects of selected cytokines and cytokine antagonists on the functional properties of DRG neurons including IH activity, and correlate these effects to behavioral measures of hyperalgesia and allodynia. By balancing the cytokine profiles in the DRG, we hope to prevent the development of hyperexcitability of DRG neurons and reduce the pain and hyperalgesia in animal models. Results will provide new insights into the mechanism of intractable pathologic pain, and suggest new therapeutic targets. Chronic pain conditions are common, long-lasting, and debilitating. We propose to study the newly recognized role of inflammation in chronic pain. Using a rat model, we will determine how inflammation directly affects the neurons that sense pain.

描述（由申请人提供）：拟议的实验将检查背根神经节（DRG）中炎症反应在病理性疼痛的发生和持续中的作用。在经常与急性或慢性疼痛相关的各种临床病症后，在 DRG 中观察到炎症反应：腰椎间盘突出/破裂、机械压迫、病毒感染（例如带状疱疹、HIV 感染）和周围神经损伤。大多数慢性疼痛炎症研究都集中在脊髓、大脑和周围神经。然而，尚不清楚长期炎症如何影响初级感觉神经元的功能或电生理特性、炎症刺激后背根神经节中的细胞因子谱如何变化，以及哪些细胞因子在病理性疼痛状态的引发和持续中最重要。我们开发了一种新的大鼠背根神经节局部炎症模型。该模型显示出长时间的疼痛行为、自发活动以及许多不同细胞因子的变化，这些变化与机械压迫引起的类似。新模型使我们能够在没有其他类型神经损伤的情况下检查炎症本身的影响。我们假设发炎的 DRG 中感觉神经元的功能特性改变以及随后的病理性疼痛至少可以部分归因于 DRG 内细胞因子表达不平衡导致的超极化激活电流（HCN 或 IH）活性的改变。使用机械压缩和 DRG 炎症模型，我们将通过 3 个特定目标 (SA) 检验我们的假设。 SA1：识别局部发炎的 DRG 中显着改变的细胞因子/趋化因子。 SA2。评估直接和长期炎症刺激后 DRG 神经元电生理特性的变化，并确定 IH 是否在兴奋性和自发活动增加中发挥重要作用。 SA3。操纵体内关键细胞因子（在 SA1 中鉴定）的水平，以确定它们对疼痛行为的贡献以及神经元电特性的潜在变化。使用我们之前开发的 DRG 体内长期灌注方法，我们将研究选定的细胞因子和细胞因子拮抗剂对 DRG 神经元功能特性（包括 IH 活性）的影响，并将这些影响与痛觉过敏和异常性疼痛的行为测量相关联。通过平衡 DRG 中的细胞因子谱，我们希望防止 DRG 神经元过度兴奋的发展，并减少动物模型中的疼痛和痛觉过敏。结果将为顽固性病理性疼痛的机制提供新的见解，并提出新的治疗靶点。慢性疼痛很常见、持久且使人衰弱。我们建议研究新近认识到的炎症在慢性疼痛中的作用。使用大鼠模型，我们将确定炎症如何直接影响感知疼痛的神经元。