PRG‐1 Relieves Neonatal Stimuli‐Induced Hyperalgesia and Anxiety via Stage‐Specific Synapse Remodeling

Objective Neonatal repetitive noxious stimuli (RNS), to mimic early‐life repetitive pain exposure, induce persistent hyperalgesia, anxiety‐like behaviors and postoperative pain sensitization that endure into adulthood. These long‐term neurobehavioral abnormalities are associated with impaired cognitive, emotional, and psychosocial functions. Method We established a neonatal RNS rat model through repetitive needle pricks to all four limbs of neonatal rats and investigated the effects of hippocampal PRG‐1 and synaptic remodeling at different stages in RNS rat. Results Our study demonstrates that hippocampal PRG‐1 dynamically modulates RNS‐induced hyperalgesia and anxiety through stage‐specific regulation of AMPAR GluR1/GluR2 and NMDAR GluN2A/GluN2B trafficking, which leads to synaptic remodeling via altered dendritic synaptic morphology and synaptic transmission efficacy. Conclusion Our findings suggest that PRG‐1 relieves RNS‐induced persistent hyperalgesia, anxiety, and pain‐perception memory via synapse remodeling at different stages. Targeting PRG‐1‐mediated synaptic remodeling may provide a novel neuroprotective strategy for preventing chronic pain comorbidities with anxiety disorders following early‐life pain exposure.