Mice with postsurgical pain exhibit age-dependent spinal microglial activation and inhibitory synapse loss

Persistent postsurgical pain is a major clinical concern, especially in the aging population, who represent a growing proportion of surgical patients. Although age is a known pain risk factor, the mechanisms driving age-related vulnerability to chronic postoperative pain remain poorly understood. This study aims to investigate how aging influences the resolution of postoperative pain and to elucidate the roles of microglial activation and synaptic remodeling in the spinal dorsal horn. A plantar incision model in young (3-month-old) and aged (18-month-old) male and female mice was used to mimic postoperative pain conditions. Mechanical and thermal hypersensitivity at various postoperative intervals were assessed by von Frey and Hargreaves tests. Microglial activation and inhibitory/excitatory synaptic densities in the spinal dorsal horn were evaluated using immunofluorescence and 3D reconstruction with Imaris software. On postoperative day (POD) 3, both age groups exhibited reduced pain thresholds on the ipsilateral side, along with microglial activation in the dorsal horn. On POD 7, pain thresholds in young mice had returned to baseline with no significant microglial activation, while aged mice showed sustained reduction in pain thresholds, continuous microglial activation, and significant loss of inhibitory synapses without detectable changes in excitatory synapse density. These findings are consistent across both sexes, with no sex-related differences. Collectively, these results suggest that aging is associated with persistent postoperative pain, which correlates with microglial activation and inhibitory synapse loss. These insights advance our understanding of age-related pain vulnerability and may inform the development of more effective, targeted, and age-specific therapeutic strategies to prevent or alleviate persistent postoperative pain in elderly patients.