Astrocyte-to-neuron interaction via NF-κB/C3/C3aR mediates chronic post-thoracotomy pain by modulating neuronal GluR1 in spinal dorsal horn.

Chronic post-thoracotomy pain (CPTP) is a debilitating postoperative complication associated with persistent hypersensitivity and neuroinflammatory changes. Here, we identify an astrocyte-neuron signaling cascade mediated by NF-κB/C3/C3aR that drives excitatory synaptic remodeling in the spinal dorsal horn during CPTP. Using a rat model, we show that the activation of astroglial NF-κB promotes C3 synthesis, which interacts with neuronal C3aR to enhance GluR1 expression and synaptic localization, thereby facilitating pain hypersensitivity. The pharmacological inhibition of NF-κB or knockdown of astroglial C3 or neuronal C3aR markedly attenuated mechanical and cold allodynia, accompanied by reduced GluR1 expression. These findings define a mechanistic link between glial NF-κB activation, complement signaling, and neuronal excitatory transmission, highlighting the NF-κB/C3/C3aR pathway as a potential therapeutic target for chronic postoperative pain.