Effect of Articular Neurotoxin on Joint Pain and Neurochemical Signature

 描述(由申请人提供)： 关节炎影响着世界上10%的人口。疼痛是关节炎最常见的症状，可以是严重的和致残的。人们对关节炎疼痛的原因知之甚少，许多患者的治疗方法往往无效、危险或无法获得。最近在了解其他类型的疼痛方面的进展导致了对这些类型的疼痛的有效的具体治疗。关节炎的研究以前只集中在关节破坏的机制上，而不是理解关节炎疼痛。我们使用急性和慢性关节炎的小鼠模型来研究关节内神经毒素(NT)用于缓解关节炎疼痛的止痛潜力。 改善肌肉骨骼功能。我们对肉毒杆菌毒素的研究结果表明，它对减轻小鼠慢性关节炎疼痛有效，但对急性关节炎疼痛效果较差。我们计划使用我们已建立的研究关节炎疼痛行为的方法和神经免疫组织化学方法来研究其他关节内神经毒素对关节炎小鼠模型关节炎疼痛的影响。我们的长期目标是发现与目前治疗慢性关节炎疼痛的现有疗法相比，可以联合使用并在当地提供更好安全性和有效性的神经毒素疗法。NT筛查研究将使用急性炎症以及持续性炎症和退行性关节炎模型进行。这些模型将分别通过向小鼠膝关节注射角叉菜胶、完全弗氏佐剂和破坏膝关节内侧半月板的方法来制作。我们可以通过使用可视视频步态分析评分系统来观察和量化自发的疼痛行为，如夜间跑轮和自发的夜间活动，以及诱导的行为，如发声，按压疼痛的关节时咬人和与操作者打架，以及由于疼痛而导致的步态异常，来衡量关节炎的疼痛行为。我们将比较神经毒素，如关节内辣椒素，树脂毒素和碘树脂毒素的止痛效果，与标准止痛药，如吗啡，使用这些指标的压痛，疼痛行为，活动和步态。除了疼痛和止痛的行为测量外，我们还将通过检测神经损伤、炎症的标记物以及关节周围神经以及背根节和脊髓中重要的伤害性神经肽的表达来检查急性和慢性关节炎疼痛的神经生物学特征。我们还将使用同样的技术将止痛效果与这些变化联系起来。两种最有效的止痛药NT将在两种慢性关节炎模型中进行详细研究，以确定最佳有效剂量和时间进程。在动物模型中测试新的疼痛疗法，如关节内NTS，并确定它们对神经系统生物学的影响的能力，将使我们能够迅速实现我们的目标，即确定潜在的相关疗法 许多人患有致残性慢性关节炎疼痛。

 DESCRIPTION (provided by applicant): Arthritis affects 10% of the world's population. Pain, the most common symptom of arthritis, can be severe and disabling. The causes of arthritis pain are poorly understood and treatments are often ineffective, dangerous, or unavailable to many sufferers. Recent advances in the understanding of other types of pain have lead to effective specific treatments for those types of pain. Arthritis research previously has focused only on mechanisms of joint destruction and not on understanding arthritis pain. We have used mouse models of acute and chronic arthritis to study the analgesic potential of intra-articular (IA) neurotoxins (NT) for relieving arthritis pain and improving musculoskeletal function. The results of our studies with Botulinum toxin and shown that it is effective for reducing chronic arthritis pain in mice but is less effective for acte arthritis pain. We plan to use our established methods for studying arthritis pain behaviors and neuroimmuno-histochemistry to study the effects of other intra-articular neurotoxins on arthritis pain in murine models of arthritis. Our long-term goal is to discover neurotoxin therapies that could be used in combination and delivered locally with better safety and efficacy than currently available therapies for chronic arthritis pain. NT screening studies will be carried out using an acute inflammatory as well as persistent inflammatory and degenerative arthritis models. These models will be produced by injecting mouse knee joints with carrageenan, and Complete Freund's Adjuvant and by destabilizing the medial meniscus of the knee respectively. We can measure arthritis pain behaviors by observing and quantifying spontaneous pain behaviors such as nocturnal wheel-running and spontaneous nocturnal activity, as well as induced behaviors such as vocalizations, biting and fighting the handler when pressing on the painful joint and gait abnormalities due to pain using a visual video gait analysis scoring system. We will compare the analgesic effect of neurotoxins such as intra-articular capsaicin, resiniferatoxin and iodo-resiniferatoxin to standard pain medications such as morphine using these measures of tenderness, pain behavior, activity and gait. In addition to behavioral measures of pain and analgesia, we will examine the neurobiological signature of acute and chronic arthritis pain by examining markers of neural injury, inflammation and the expression of neuropeptides important for nociception in the peripheral nerves of the joint as well as in the DRG and spinal cord. We will also correlate the effect of analgesia with these changes using these same techniques. The two most effective analgesic NT will be studied in detail in the two chronic arthritis models to determine optimum effective dose and time course. The ability to test novel pain therapies such as intra-articular NTs in an animal model and to determine their effect on nervous system biology will allow us to quickly achieve our goal of identifying potentially relavent therapies for the many people with disabling chronic arthritis pain.