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，可能很严重，甚至致残。关节炎疼痛的原因知之甚少，治疗往往是无效的，危险的，或无法获得许多患者。对其他类型疼痛的理解的最新进展导致了对这些类型疼痛的有效特定治疗。 关节炎的研究以前只集中在关节破坏的机制，而不是了解关节炎疼痛。我们使用小鼠急性和慢性关节炎模型来研究关节内（IA）神经毒素（NT）缓解关节炎疼痛的镇痛潜力 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。我们计划使用我们建立的研究关节炎疼痛行为和神经免疫组织化学的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可以联合使用的神经毒素疗法，并在局部提供比目前可用的慢性关节炎疼痛疗法更好的安全性和有效性。 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NT筛选研究。这些模型将分别通过用角叉菜胶和完全弗氏佐剂注射小鼠膝关节以及通过使膝关节的内侧半月板不稳定来产生。我们可以通过观察和量化自发性疼痛行为，如夜间轮运行和自发性夜间活动，以及诱导行为，如发声，咬和战斗处理器时，按下疼痛的关节和步态异常由于疼痛，使用视觉视频步态分析评分系统来测量关节炎疼痛行为。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镇痛效果，标准的止痛药，如吗啡使用这些措施的压痛，疼痛行为，活动和步态。除了疼痛和镇痛的行为措施，我们将检查急性和慢性关节炎疼痛的神经生物学特征，通过检查神经损伤，炎症和神经肽的表达的标志物，对关节周围神经以及背根神经节和脊髓的伤害性感受很重要。我们还将使用这些相同的技术将镇痛效果与这些变化相关联。将在两种慢性关节炎模型中详细研究两种最有效的镇痛NT，以确定最佳有效剂量和时间过程。 在动物模型中测试新型疼痛疗法（如关节内NT）并确定其对神经系统生物学的影响的能力将使我们能够快速实现识别潜在相关疗法的目标， 许多患有慢性关节炎疼痛的人。

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.