Abstract
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.