Synaptic-immune interactions in neuropathic pain: complement-mediated remodeling of spinal dorsal horn microcircuits

Neuropathic pain (NP) has long been considered to arise primarily from abnormal neuronal excitability and ion channel dysfunction. However, accumulating evidence indicates that structural and functional remodeling of microcircuits in the spinal dorsal horn (SDH) also plays a critical role in the initiation and maintenance of pain. This article reviews and integrates recent findings demonstrating that aberrant activation of the complement system in the mature central nervous system preferentially targets inhibitory synapses and their microenvironment through microglia-mediated synaptic pruning. Disruption of perineuronal nets, remodeling of synaptic surface glycocodes, and activity-dependent complement deposition collectively increase the vulnerability of inhibitory circuits to immune-mediated elimination. These processes interact with alterations in ionic homeostasis, including downregulation of KCC2 and polarity shifts in GABAergic transmission, thereby promoting disinhibition, central sensitization, and impairment of sensory gating. Importantly, complement-driven synaptic remodeling is not an isolated inflammatory event but rather the outcome of coordinated regulation within a neuron-glia-immune network. This perspective helps explain the limited efficacy of neuron-centered analgesic strategies and provides a theoretical basis for the development of disease-modifying therapies aimed at synaptic preservation and stabilization of the synaptic microenvironment.