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

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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.