Effect of Articular Neurotoxin on Joint Pain and Neurochemical Signature

关节神经毒素对关节疼痛和神经化学特征的影响

基本信息

批准号：
10554234
负责人：
HOLLIS Elaine KRUG
金额：
--
依托单位：
MINNEAPOLIS VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10554234
关键词：
Absence of pain sensation Acute Affect Agonist Analgesics Animal Model Arthralgia Arthritis Behavior Botulinum Toxin Type A Botulinum Toxins Botulism Capsaicin Carrageenan Chronic Combined Modality Therapy Dangerousness Degenerative polyarthritis Dose Effectiveness Freund&apos s Adjuvant Funding Gait Gait abnormality Goals Histocytochemistry Human Immunohistochemistry Individual Inflammation Inflammatory Inflammatory Arthritis Injections Intra-Articular Injections Joints Knee Knee joint Lead Measures Medial meniscus structure Methods Microscopic Modeling Molecular Molecular Analysis Morphine Mus Musculoskeletal Nerve Nervous system structure Neurobiology Neuropeptides Neurotoxins Nociception Pain Pain management Peripheral Nerves Persons Plant Extracts Population Regimen Research Resiniferatoxin Running Safety Spinal Cord Standardization Sympathetic Ganglia System Systems Biology TRPV1 gene Techniques Testing Time Tissues Toxin Vanilloid Visual Work antagonist arthritic pain base behavior measurement common symptom comparative efficacy effective therapy fighting gait examination improved iodoresiniferatoxin joint destruction mouse model nerve injury neurochemistry neurotoxic novel pain behavior pain model pain reduction public health relevance response screening spontaneous pain treatment effect treatment group treatment strategy vocalization

项目摘要

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.

描述（由申请人提供）：关节炎影响着世界 10% 的人口，疼痛是关节炎最常见的症状，人们对关节炎疼痛的原因知之甚少，而且治疗方法往往无效、危险，或者对许多患者来说是无法获得的。对其他类型疼痛的了解有助于对这些类型的疼痛进行有效的具体治疗。以前的关节炎研究仅关注关节破坏的机制，而不是了解关节炎疼痛。我们使用急性和慢性关节炎的小鼠模型来研究镇痛。潜在的关节内 (IA) 神经毒素 (NT) 用于缓解关节炎疼痛我们对肉毒杆菌毒素的研究结果表明，它可以有效减轻小鼠的慢性关节炎疼痛，但对急性关节炎疼痛效果较差，我们计划使用我们既定的方法来研究关节炎疼痛行为和神经免疫。我们的长期目标是发现可以联合使用并以更好的安全性和局部给药方式进行局部给药的神经毒素疗法。 NT 筛选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，这些模型将通过向小鼠膝关节注射角叉菜胶和完全弗氏佐剂来产生。我们可以通过观察和量化自发疼痛行为（例如夜间跑轮和自发夜间活动）以及诱发行为（例如）来测量关节炎疼痛行为。使用视觉视频步态分析评分系统，在按压疼痛关节时发声、咬伤和对抗处理者以及由于疼痛导致的步态异常。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。除了疼痛和镇痛的行为测量之外，我们还将检查使用压痛、疼痛行为、活动和步态的这些措施的吗啡等止痛药。通过检查神经损伤标记物、炎症和对关节周围神经以及背根神经节和脊髓伤害感受重要的神经肽的表达，我们还将关联镇痛效果。将使用相同的技术对两种最有效的镇痛 NT 进行详细研究，以确定最佳有效剂量和时间过程，以测试新型疼痛疗法（例如关节内 NT）的能力。动物模型并确定它们对神经系统生物学的影响将使我们能够快速实现确定潜在相关疗法的目标许多人患有慢性关节炎疼痛。