Abstract:Neonatal surgical trauma can lead to persistent pain hypersensitivity during adulthood. The underlying spinal mechanism includes changes of synaptic plasticity, as well as the impact of glial-neuronal interactions on synaptic structure and function. Structurally, microglia selectively phagocytose inhibitory synapses in an age-dependent manner, dismantling spinal gate control. Functionally, molecules in microglia, such as purinergic receptor and brain-derived neurotrophic factor (BDNF), enhance excitatory synaptic transmission via downstream pathways, facilitating long-term potentiation (LTP) and weakening inhibitory tone, forming a self-reinforcing pain circuit. The initiation of this network displays significant male predominance, while protective mechanisms in females remain undefined. Current preventive and therapeutic strategies, including nerve blocks, microglial inhibitors, and serotonergic modulation, face three major bottlenecks: the species gap in translating findings from rodent models to human neonates, the systematic lack of sex-specific interventions for females, and the developmental risks of globally inhibiting core targets such as BDNF. Future research should establish humanized models to validate key pathways, systematically elucidate the molecular basis of sex differences, and prioritize the exploration of peripheral nerve interventions to retrogradely regulate central mechanisms. This will enable safe, precise neuroprotection and advance the field from mechanistic understanding toward clinical improvement of neonatal pain.
