Sex differences in the temporal development of pronociceptive immune responses in the tibia fracture mouse model

Previously, distinct sex differences were observed in the pronociceptive role of spinal immune cells in neuropathic and inflammatory mouse pain models. Both peripheral and central innate and adaptive immune changes contribute to sensitization in the tibia fracture rodent model of complex regional pain syndrome, and the current study evaluated sex differences in the development of pronociceptive immune responses after fracture. At 4 and 7 weeks after fracture, the analgesic effects of a microglia inhibitor were tested in male and female mice, and polymerase chain reaction was used to measure inflammatory mediator expression in skin and spinal cord. The temporal progression of complex regional pain syndrome-like changes in male and female wild-type and muMT fracture mice lacking B cells and antibodies were evaluated, and IgM antibody deposition measured. Pronociceptive effects of injecting wild-type fracture mouse serum into muMT fracture mice were also tested in both sexes, and the role of sex hormones was evaluated in the postfracture development of pronociceptive immune responses. Long-lasting immune changes developed in the fracture limb and corresponding spinal cord of both male and female mice, including upregulated neuropeptide and cytokine signaling, microglial activation, and pronociceptive autoimmunity. These complex postfracture immune responses were sexually dichotomous and interacted in temporally evolving patterns that generated post-traumatic nociceptive sensitization in both sexes lasting for up to 5 months. Unfortunately, the redundancy and plasticity of these chronic post-traumatic immune responses suggest that clinical interventions focusing on any single specific pronociceptive immune change are likely to be ineffectual.