NEURAL AND CHEMICAL BASIS OF PATHOLOGIC PAIN

病理性疼痛的神经和化学基础

• 批准号: 8013533
• 负责人: Jun-Ming Zhang
• 金额: $ 33.44万
• 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/8013533
• 关键词: Accounting; Acute; Acute Pain; Address; Adult; Affect; Afferent Neurons; Animal Model; Behavioral; Brain; Cell Size; Cells; Chemicals; Clinical; Data; Development; Electric Capacitance; Equilibrium; Fiber; Fire - disasters; Frequencies; Ganglia; HIV Infections; Herpes zoster disease; Hyperalgesia; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Investigation; Ion Channel; Ions; Measures; Mechanics; Mediating; Membrane; Methods; Modeling; Nerve; Neurons; Pain; Pathologic; Perfusion; Peripheral; Peripheral Nerves; Peripheral nerve injury; Physiological; Play; Principal Investigator; Property; Published Comment; Rattus; Research; Research Personnel; Role; Rupture; Screening procedure; Spinal Cord; Spinal Ganglia; Suggestion; Testing; Time; Topical application; Up-Regulation; Virus Diseases; Work; Writing; allodynia; base; behavior measurement; cell type; chemokine; chronic pain; cytokine; density; design; electrical property; improved; in vivo; insight; interdisciplinary approach; interest; irritation; nerve injury; new therapeutic target; novel; pain behavior; prevent; programs; receptor; relating to nervous system; research study; response; voltage; 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）：拟议的实验将检查炎症反应在背根神经节（DRG）中在病理疼痛的发育和持久性中的作用。在DRG中已经观察到炎症反应在各种临床状况下通常与急性或慢性疼痛有关：腰椎间盘突出症/破裂，机械压缩，病毒感染（例如，带状疱疹，HIV，HIV感染）和周围神经损伤。慢性疼痛中炎症的大多数研究都集中在脊髓，大脑和周围神经上。但是，尚不清楚延长炎症如何影响原发性感觉神经元的功能或电生理特性，炎症刺激后DRG的细胞因子特征如何变化，以及哪些细胞因子在病理疼痛状态的启动和持久性中最重要。我们已经开发了一种新的DRG局部炎症的大鼠模型。该模型显示了长时间的疼痛行为，自发活性以及许多与机械压缩引起的细胞因子相似的细胞因子的变化。在没有其他类型的神经损伤的情况下，新模型使我们能够检查炎症本身的影响。我们假设在发炎的DRG中，感觉神经元的功能特性改变了，并且随后的病理疼痛至少可以通过DRG中的细胞因子表达不平衡的过度激活电流（HCN或IH）的活性来部分解释。使用机械压缩和DRG炎症模型，我们将通过3个特定目标（SA）检验假设。 SA1：确定局部发炎的DRG中的细胞因子/趋化因子明显改变。 SA2。评估直接和长时间炎症性刺激后DRG神经元电生理特性的变化，并确定IH在增加的兴奋性和自发活性中是否起重要作用。 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性能的潜在变化。使用先前开发的DRG体内体内灌注的方法，我们将研究选定的细胞因子和细胞因子拮抗剂对包括IH活性在内的DRG神经元功能特性的影响，并将这些影响与Hyperalgesia和Alydrodynia的行为度量相关。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，并减轻动物模型中的疼痛和痛觉过敏。结果将为顽固性病理疼痛的机制提供新的见解，并提出新的治疗靶标。慢性疼痛状况是常见的，持久的，并且使人衰弱。我们建议研究炎症在慢性疼痛中的新认识的作用。使用大鼠模型，我们将确定炎症如何直接影响疼痛的神经元。