NEURAL AND CHEMICAL BASIS OF PATHOLOGIC 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。在通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）和外周神经损伤。大多数关于慢性疼痛炎症的研究集中在脊髓、脑和外周神经。然而，目前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DRG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起始和持续中最重要。我们建立了一种新的大鼠DRG局部炎症模型。该模型显示出延长的疼痛行为、自发活动和许多不同细胞因子的变化，这些变化与机械压迫诱导的变化相似。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，在发炎的背根神经节和随后的病理性疼痛的感觉神经元的功能特性的改变，可以至少部分地占超极化激活电流（HCN或IH）的活动改变，导致不平衡的细胞因子表达的背根神经节内。使用机械压迫和DRG炎症模型，我们将通过3个特定目标（SA）来检验我们的假设。SA 1：识别局部炎症的背根神经节中显着改变的细胞因子/趋化因子。SA 2.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起重要作用。SA 3.操纵体内关键细胞因子（在SA 1中鉴定）的水平，以确定它们对疼痛行为的贡献和神经元电特性的潜在变化。使用我们以前开发的方法，在DRG的长期体内灌注，我们将研究选定的细胞因子和细胞因子拮抗剂的DRG神经元的功能特性，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措施。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。这些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。慢性疼痛状况是常见的，持久的，使人衰弱的。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感知疼痛的神经元。

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.