S-ketamine relieves neuropathic pain by inhibiting microglia phagocytosis of the perineuronal nets

Perineurial network (PNN) is a special extracellular matrix structure in the central nervous system, and its alterations are associated with the pain hypersensitivity. Recent studies have suggested a potential interaction between abnormal activation of spinal microglia and PNN. This study investigates whether S-ketamine mitigates neuropathic pain via inhibiting degradation of PNNs by spinal microglia. C57BL/6 mice were utilized for CCI modeling to induce neuropathic pain. Subsequent to modeling, we assessed the expression changes of spinal microglia, PNN and inflammatory factors. Microglia colocalization with PNN was evaluated via 3D reconstruction to quantify spatial overlap. Minocycline was administered to target microglia. S-ketamine was subsequently administered to CCI mice, and its effects on pain behavior, microglial activation, and PNN were investigated. Microglia-PNN colocalization was evaluated via 3D reconstruction to quantify spatial overlap. CCI mice exhibited significant neuropathic pain, accompanied by increased microglia-mediated phagocytosis of PNN. Minocycline and S-ketamine treatment of CCI mice led to improved pain thresholds, suppression of neuroinflammation, and reduction in microglia-mediated phagocytosis of PNN. Increased microglial phagocytosis leading to PNNs degradation in the spinal dorsal horn plays a critical role in neuropathic pain pathogenesis. The analgesic effects of S-ketamine may be attributed to its modulation of this mechanism.