(847) Pain Perceptions in Neurodevelopmental Disorders: Evaluation in a Mouse Model of Rett Syndrome

Introduction: Studying pain responses in neurodevelopmental disorders is challenging due to communication barriers, cognitive impairments, and abnormal sensory perceptions. This study aims to assess alterations in pain perception with disease progression in a clinically relevant mouse model of Rett Syndrome (RTT). RTT is an X-linked disorder caused by deletions in the methyl-CpG binding protein 2 gene (MECP2), characterized by developmental regression, cognitive dysfunction, and seizures. Case reports suggest atypical pain perception in patients with RTT, but clinical studies have been inconclusive, reporting both hypoalgesia and hyperalgesia. Speculations point to alterations in the MeCP2 protein as a potential mechanism underlying pain modulation in RTT, and a better understanding is vital for future therapeutic studies.

Methods: MeCP2-/+ female mice and age-matched wild-type female littermates were evaluated at two ages: 6-8 weeks (asymptomatic) and 4 months (symptomatic). Phenotype was assessed using a neurobehavioral score and Catwalk Gait analysis. Pain sensitivity and thresholds were assessed to mechanical (Von Frey test) and heat (Hargreaves test) stimuli. At both time points, neuronal staining was performed on lumbar spinal cord tissue, including the dorsal root ganglion.

Results: MeCP2-/+ mice showed variation in pain sensitivity with disease progression. Asymptomatic mice were hypersensitive to both mechanical and thermal pain, shown by increased responses to Von Frey filament testing and decreased paw withdrawal latency on thermal Hargreaves testing. With the progression of disease, MeCP2-/+ mice became hyposensitive to both mechanical and thermal pain, independent of their motor ability. We are currently evaluating neuronal changes over time to identify mechanisms that could explain this finding.

Conclusions: MeCP2-/+ female mice represent a useful preclinical RTT model. They exhibit abnormal pain behavior, with initial hyperalgesia and eventual hypoalgesia independent of motor function. MECP2 overexpression has been associated with increased pain tolerance and lack of MECP2 may contribute to the early pain hypersensitivity and potential hypoalgesia with progressive neurodegeneration. Understanding these changes in pain perception will aid in optimizing pain management in patients with RTT.