Validation of Prenatal Rabbit Hypoxia Ischemia as a Model of Cerebral Palsy-induced Pain

产前兔缺氧缺血作为脑瘫引起的疼痛模型的验证

• 批准号: 10813313
• 负责人: MEGAN R DETLOFF
• 金额: $ 272.7万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10813313
• 关键词: ARHGEF5 gene; Address; Affect; Age; Aging; Anatomy; Animal Model; Anxiety; Area; Arthritis; Behavior; Behavior assessment; Birth; Brain; Brain Hypoxia-Ischemia; Brain Injuries; CDK6-associated protein p18; Cerebral Palsy; Chronic; Classification; Clinical; Cognition; Conflict (Psychology); Contracture; Data; Databases; Development; Etiology; Event; Exhibits; Experimental Models; Face; Family; Fiber; Functional disorder; Hand; Hip region structure; Histology; Hyperalgesia; Hyperreflexia; Hypersensitivity; Hypoxia; Impairment; Individual; Infection; Inflammation; Injury; Ischemia; Joints; Knowledge; Leporidae; Link; Lower Extremity; Measurement; Measures; Mechanics; Medical; Mental Depression; Modeling; Morbidity - disease rate; Motor; Movement; Multivariate Analysis; Muscle; Muscle Hypertonia; Muscle Spasticity; Musculoskeletal; Musculoskeletal Pain; Nature; Nerve Fibers; Neurons; Neuropathy; New Zealand; Nociception; Nociceptors; Oryctolagus cuniculus; Outcome; Pain; Pain Measurement; Pain management; Pathway interactions; Patient Self-Report; Perinatal; Perinatal Hypoxia; Peripheral; Persons; Pharmaceutical Preparations; Phenotype; Physiological; Placental Insufficiency; Pregnancy; Procedures; Psychological Stress; Quality of life; Reporting; Reproducibility; Research; Research Personnel; Rodent; Rodent Model; Schizophrenia; Sensory; Severities; Site; Spastic Cerebral Palsy; Spinal Cord; Stress; Sucrose; Surgeon; Syndrome; System; Testing; Torque; Training; Validation; Validity and Reliability; anxiety-like behavior; autism spectrum disorder; biopsychosocial; chronic pain; chronic pain patient; comorbidity; comparative; density; depressive symptoms; detection sensitivity; disability; experience; experimental group; foot; gabapentin; motor deficit; motor disorder; motor impairment; neonate; neural; novel; object recognition; pain perception; pain relief; pain sensitivity; painful neuropathy; patch clamp; physical insult; postnatal; preclinical study; preference; prenatal; prescription opioid; sex; spastic paralysis; subluxation; therapeutic target; validation studies; virtual; white matter injury

Project Summary / Abstract Cerebral palsy (CP) is a condition defined by motor impairment, but pain is the most prevalent co-morbidity. Pain is commonly attributed to stiff, spastic muscles, joint contractures, hip subluxation and arthritis. However, the presence of chronic pain does not neatly correlate with severity of musculoskeletal problems and may be entirely independent (ie thermal hypersensitivity). CP associated pain can be both nociplastic and neuropathic in nature and could be caused by the same global neural damage that disrupted movement. Research on pain in CP requires using an animal model that displays both phenotypes of motor dysfunction and enhanced pain. We address this clinical need by validating a larger, non-rodent animal model of CP which exhibits both sensory and motor impairments after prenatal hypoxia. New Zealand White (NZW) rabbits (family Leporidae) have higher face, construct and criterion validity than rodent models of CP and are widely used for comparative preclinical studies of CP. Recent data from our labs reveal these rabbits also have enhanced nociception. We propose to further validate HI rabbits as a model of chronic pain in CP, an area that is completely unstudied. Aim 1 Determine face validity of HI rabbits as a model of CP-associated pain. Anatomical and physiological evidence of musculoskeletal pain, nociplastic pain and neuropathic pain will be assessed in naïve control, HI affected, and sham-operated rabbit kits from birth to sexual maturity (at P5, P18, P60, P180). We will characterize nociceptor dysfunction using patch clamp of DRG neurons (n = 100 neurons from 10 rabbits per age per experimental group), histology of peripheral nociceptors (sprouting of central afferent fibers, counts of nociceptors in the DRGs, and epidermal nerve fiber density in 6 kits per age per experimental group), and musculoskeletal impairment (modified Ashworth, joint torque and muscle shortening in all kits in Aims 1-2). Aim 2 Validate that sensory behavior in HI rabbits is consistent with pain phenotypes in CP. We will build upon our initial studies on nociception in neonates to verify the progression of behaviors related to biopsychosocial pain during aging. Specifically, we will perform tests of nociception, pain perception, cognition, and depressive- and anxiety-like behaviors in 20 kits per sex per experimental group, measured longitudinally as in Aim 1. A multivariate analysis will compare measures in control, sham and HI affected groups, sex and severity of motor deficits. All tests will be assessed for reliability and validity. The most efficient and valid procedures will be identified to maintain high sensitivity for detection of pain. These tests will determine if HI rabbits show robust, reproducible behaviors indicative of the multifaceted pain similar to people with CP. Aim 3 Determine reproducibility and reliability of the rabbit HI model of CP for studies of pain. Model reproducibility will be determined by having experienced surgeons, caretakers, and behaviorists train novice investigators. Inter-experimenter reliability will be assessed in all procedures and assessments in Aims 1 - 2. Together, these tests will provide a validation of the HI rabbit for use in studies of pain in the context of CP.

项目摘要 /摘要 脑瘫（CP）是由运动障碍定义的疾病，但疼痛是最普遍的合并症。 疼痛通常归因于僵硬的痉挛性肌肉，关节染色，髋关节脱位和关节炎。然而， 慢性疼痛的存在与肌肉骨骼问题的严重程度不整洁，可能是 完全独立（即热超敏反应）。 CP相关的疼痛既可以是鼻虫和神经性疼痛 本质上，可能是由破坏运动的全球中性损害引起的。疼痛研究 在CP中，需要使用动物模型，该模型既显示运动功能障碍的表型又显示出疼痛的增强。 我们通过验证更大的非塑性动物CP模型来满足这种临床需求 产前缺氧后感觉和运动障碍。新西兰白人（NZW）兔子（家庭鳞翅目） 与CP的啮齿动物模型相比，具有更高的面部，构造和标准有效性，并广泛用于比较 CP的临床前研究。我们实验室的最新数据显示，这些兔子也具有增强的伤害感受。我们 提出进一步验证HI兔子作为CP慢性疼痛模型的建议，该区域是完全未经研究的。 AIM 1确定HI兔子作为CP相关疼痛模型的面部有效性。解剖学和 将评估肌肉骨骼疼痛，肿瘤疼痛和神经性疼痛的生理证据。 从出生到性成熟度，控制，HI受影响和假手术兔子套件（P5，P18，P60，P180）。我们 将使用DRG神经元的斑块夹（n = 10个兔子的100个神经元）来表征伤害感受器的功能障碍 每个实验组的每个年龄），周围伤害感受器的组织学（中央传入纤维的发芽，计数 DRG中的伤害感受器，每个实验组的6套盒中的表皮神经纤维密度）和 AIMS 1-2中所有套件中所有套件的修饰的Ashworth，关节扭矩和肌肉缩短的肌肉骨骼障碍。 AIM 2验证HI兔子中的感觉行为与CP中的疼痛表型一致。我们将 基于我们对新生儿伤害感受的最初研究，以验证与 衰老期间的生物心理社会疼痛。具体而言，我们将进行伤害感受，疼痛感知，认知， 每个实验组的抑郁症和类似动画的行为，以20套件为单位，纵向测量 与AIM 1一样。多元分析将比较控制，假和HI受影响的群体，性别和性别的措施 运动缺陷的严重程度。所有测试将均可评估可靠性和有效性。最有效，最有效的 将确定程序以保持高灵敏度以检测疼痛。这些测试将确定是否嗨 兔子表现出强大的可再现行为，表明与CP患者相似的多方面疼痛。目标3 确定CP兔子HI模型的可重复性和可靠性，以进行疼痛研究。模型 可重复性将由经验丰富的外科医生，看护人和行为主义者训练小说来确定 调查人员。实验者间的可靠性将在目标1-2中的所有程序和评估中进行评估。 总之，这些测试将提供对HI兔子的验证，以在CP的背景下用于疼痛研究。