Sex-specific molecular and cellular phenotypes during resolution of neuropathic pain in dorsal root ganglia

The dorsal root ganglion (DRG) is examined for sex-dependent phenotypes in sensory neurons, satellite glial cells (SGCs), and local macrophages following traumatic nerve injury and during natural pain resolution. Systematic analysis of 7,495 DRG immunofluorescence images and 62 transcriptomes reveals pronounced sex-specific, multicellular DRG phenotypes, particularly during pain resolution. Tissue size and neuron density also show sex-dependent differences. Neuropathic pain is resolved without tissue or sensory neuron loss. After injury, macrophages localize to the space between sensory neurons and SGCs; this effect is partially reversed during pain resolution, particularly in males. In females, immune-related gene expression and macrophage phenotypes persist longer, while SGC activation and contact with sensory neurons are more persistent in males. During resolution, synaptic and excitability-related processes are marked in both sexes. In summary, injury responses were largely shared between sexes, whereas the resolution phase exhibited distinctly sex-specific molecular and cellular signatures.