This study investigates the immune mechanisms underlying inflammatory pain by analyzing single-cell transcriptomics in three skin inflammatory pain models in mice: zymosan injection, skin incision, and ultraviolet (UV) burn. The authors found that macrophage and neutrophil recruitment closely mirrored the kinetics of pain development, with distinct cell-type-specific transcriptional programs associated with pain and its resolution. Using a comprehensive list of potential interactions mediated by receptors, ligands, ion channels, and metabolites, they identified thrombospondin-1 (TSP-1), upregulated by immune cells upon injury, as an inhibitor of nociceptor sensitization. The study provides a foundation for identifying neuroimmune axes that modulate pain in diverse disease contexts. Key findings include the correlation between immune infiltration and pain development, the transcriptional changes in macrophages mirroring pain hypersensitivity, and the role of TSP-1 in counteracting nociceptor sensitization. The study highlights the importance of immune cell interactions in pain development and resolution, offering potential therapeutic targets for inflammatory pain.This study investigates the immune mechanisms underlying inflammatory pain by analyzing single-cell transcriptomics in three skin inflammatory pain models in mice: zymosan injection, skin incision, and ultraviolet (UV) burn. The authors found that macrophage and neutrophil recruitment closely mirrored the kinetics of pain development, with distinct cell-type-specific transcriptional programs associated with pain and its resolution. Using a comprehensive list of potential interactions mediated by receptors, ligands, ion channels, and metabolites, they identified thrombospondin-1 (TSP-1), upregulated by immune cells upon injury, as an inhibitor of nociceptor sensitization. The study provides a foundation for identifying neuroimmune axes that modulate pain in diverse disease contexts. Key findings include the correlation between immune infiltration and pain development, the transcriptional changes in macrophages mirroring pain hypersensitivity, and the role of TSP-1 in counteracting nociceptor sensitization. The study highlights the importance of immune cell interactions in pain development and resolution, offering potential therapeutic targets for inflammatory pain.