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.

项目总结/摘要 脑性瘫痪（CP）是一种由运动障碍定义的疾病，但疼痛是最常见的合并症。 疼痛通常归因于僵硬、痉挛的肌肉、关节挛缩、髋关节半脱位和关节炎。然而，在这方面， 慢性疼痛的存在与肌肉骨骼问题的严重程度并不完全相关， 完全独立（即热过敏）。CP相关疼痛可以是伤害性的和神经性的 这可能是由破坏运动的相同的全局神经损伤引起的。疼痛研究 在CP中需要使用显示运动功能障碍和增强的疼痛的表型的动物模型。 我们通过验证一个更大的非啮齿类动物CP模型来满足这一临床需求，该模型表现出两种特征： 产前缺氧后的感觉和运动障碍。新西兰白色（NZW）兔（兔科） 比啮齿动物CP模型具有更高的面孔、结构和标准有效性，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，这些兔子也有增强的伤害感受。我们 建议进一步验证HI兔作为CP慢性疼痛模型，这是一个完全未研究的领域。 目的1确定HI兔作为CP相关疼痛模型的表面效度。解剖和 肌肉骨骼疼痛、伤害性疼痛和神经性疼痛的生理学证据将在初治患者中进行评估。 对照组、HI感染组和假手术组家兔从出生到性成熟（P5、P18、P60、P180）。我们 将使用DRG神经元的膜片钳表征伤害感受器功能障碍（n = 10只兔的100个神经元 每年龄每实验组），外周伤害感受器的组织学（中枢传入纤维的发芽，计数 背根神经节中伤害性感受器的数量，以及每个实验组每个年龄6个套件中的表皮神经纤维密度），以及 肌肉骨骼损伤（目的1-2中所有套件中的改良Ashworth、关节扭矩和肌肉缩短）。 目的2证实HI家兔感觉行为与CP疼痛表型一致.我们将 建立在我们对新生儿伤害感受的初步研究基础上，以验证与 衰老过程中的生物心理社会疼痛。具体来说，我们将进行伤害感受，疼痛感知，认知， 以及抑郁和焦虑样行为，每个实验组每种性别20个试剂盒，纵向测量 如目标1。多变量分析将比较对照组、假手术组和HI影响组中的测量，性别和 运动缺陷的严重程度。所有的测试将被评估的可靠性和有效性。最有效和有效的 将确定程序以保持对疼痛检测的高灵敏度。这些测试将确定HI是否 兔子表现出健壮的、可重复的行为，表明与患有CP的人相似的多方面疼痛。目标3 确定用于疼痛研究的CP兔HI模型的可重复性和可靠性。模型 可重复性将由经验丰富的外科医生、护理人员和行为学家培训新手来确定。 investigators.将在目标1 - 2中的所有程序和评估中评估实验者间可靠性。 总之，这些试验将提供HI家兔用于CP背景下疼痛研究的验证。