A microglial SPP1-ITGB1 feedback loop sustains thalamic hyperexcitability and post-stroke pain.

Central post-stroke pain (CPSP) represents a failure of homeostatic recovery, yet how acute injury transitions to chronic pain remains elusive. While glial reactivity is a hallmark of stroke, the effectors translating this activation into sustained neuronal hyperexcitability are undefined. Here, we identify microglia-derived secreted phosphoprotein 1 (SPP1) as a key chronification switch for CPSP-like behaviors in mice. Hemorrhage-induced ATP release activates P2X7 receptors, triggering robust SPP1 expression in microglia. This engages a self-amplifying, autocrine integrin β1 (ITGB1) signaling loop that perpetuates a chemokine-rich, pro-nociceptive milieu. Optogenetic activation of this microglial state is sufficient to induce mechanical allodynia and thalamic hyperexcitability without injury. Genetic and pharmacological dissections reveal a critical temporal dissociation: while SPP1 is induced acutely, its signaling via ITGB1 is specifically required to maintain chronic pain. These findings define the SPP1-ITGB1 axis as a fundamental driver of maladaptive sensory plasticity and a promising therapeutic target for refractory central pain.