Decoupling Mechanical and Inflammatory Stimuli in Discogenic Low Back Pain

项目摘要 慢性下背痛（LBP）是肌肉骨骼疼痛、残疾和工作日损失的主要原因之一 在美国LBP与椎间盘退变高度相关。椎间盘源性疼痛 具体来说，是LBP的主要原因。慢性椎间盘源性LBP患者通常表现出异常的感觉 椎间盘深处的神经生长一旦神经出现在退变的椎间盘中， 促炎介质的复杂环境和引起刺激的动态机械负荷， 痛苦促炎介质与伤害感受器上的受体结合导致刺激阈值降低 负责动作电位产生的离子通道。而光盘的机械加载可能导致 直接刺激机械敏感离子通道，导致疼痛感。以前的工作已经探索了 然而，使用局部递送抗炎剂到椎间盘，观察到疼痛不完全缓解。没有 已经研究了靶向椎间盘中的机械感受器以减轻慢性椎间盘源性LBP。均不会及无须 研究已经能够分析出神经存在、炎症或机械负荷的作用 是引发疼痛的主要原因由于缺乏动物模型，这个问题仍然没有答案， 准确模拟人类慢性椎间盘源性LBP的表现。 综合起来，这些数据支持我们的总体假设，即椎间盘中新的伤害感受器的存在 与炎症和/或机械负荷相结合导致慢性椎间盘源性LBP，并且靶向外周 治疗可以缓解LBP。为了验证这一假设，我们建立了一个慢性椎间盘源性的动物模型， LBP表现出强烈的行为疼痛表型和椎间盘深处的神经浸润。通过使用 创新的啮齿动物模型和神经生长、炎症介质或机械传感的靶向阻断 我们将探讨神经存在、炎症和负荷在LBP中的作用。我们将使用这些信息， 开发新的方法来缓解慢性椎间盘源性LBP。此外，将在老龄动物中验证结果 更能代表人类LBP患者。拟议的工作将使用新的方法， 有针对性的神经抑制，抗炎和机械受体拮抗作用，以解耦神经的作用 存在、炎症和LBP中的机械负荷。这项工作的成果包括， 了解LBP的具体机制，为开发外周靶向疼痛奠定基础， 这是一种顽固而广泛的疾病，患病率正在上升。

PROJECT SUMMARY Chronic low back pain (LBP) is one of the major contributors to musculoskeletal pain, disability, and lost workdays in the United States. LBP is highly correlated with degeneration of the intervertebral disc. Discogenic pain, specifically, is the leading cause of LBP. Patients with chronic discogenic LBP often exhibit aberrant sensory nerve growth deep within the disc. Once nerves are present in the degenerate disc they can be subjected to a complex milieu of pro-inflammatory mediators and dynamic mechanical loads causing stimulation and therefore pain. Binding of pro-inflammatory mediators to receptors on nociceptors results in lowered stimulation thresholds of ion channels responsible for action potential generation. Whereas mechanical loading of the disc can cause direct stimulation of mechanosensitive ion channels resulting in pain sensation. Previous work has explored the use of local delivery of an anti-inflammatory to the disc, however, incomplete pain resolution was observed. No work has examined targeting mechanoreceptors in the disc to alleviate chronic discogenic LBP. Further, no studies have yet been able to parse out which the role of nerve presence, inflammation, or mechanical loading is the major contributor to emergent pain. This question remains unanswered due to a lack of animal models that accurately mimic human presentation of chronic discogenic LBP. Taken together, these data support our overarching hypothesis that the presence of new nociceptors in the disc combined with inflammation and/or mechanical loading leads to chronic discogenic LBP, and targeted peripheral therapies may alleviate LBP. To test this hypothesis, we have developed an animal model of chronic discogenic LBP that exhibits a robust behavioral pain phenotype and nerve infiltration deep within the disc. By using innovative rodent models and targeted blockade of nerve growth, inflammatory mediators or mechanical sensing we will probe the roles of nerve presence, inflammation, and loading in LBP. We will then use this information to develop novel approaches to alleviate chronic discogenic LBP. Further, findings will be validated in aged animals which are more representative of a human LBP patient. The proposed work will use novel approaches using targeted neuro-inhibition, anti-inflammatories and mechanoreceptor antagonism to decouple the role of nerve presence, inflammation, and mechanical loading in LBP. The outcomes from this work include and better understanding of the specific mechanisms of LBP, laying the foundation to develop peripherally targeted pain for an intractable and widespread condition that is increasing in prevalence.