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The Rodent Tibia Fracture Model: A Critical Review and Comparison With the Complex Regional Pain Syndrome Literature

      Highlights

      • This review compared a rodent tibia fracture model with the complex regional pain syndrome literature.
      • The tibia fracture model generated nociceptive and inflammatory symptoms resembling early complex regional pain syndrome.
      • Neuropeptide signaling and cytokine expression are upregulated after fracture.
      • Fracture activated spinal glia and induced changes in brain dendritic architecture.
      • B-cell production of immunoglobulin M autoantibodies also contributed to post-fracture pain.

      Abstract

      Distal limb fracture is the most common cause of complex regional pain syndrome (CRPS), thus the rodent tibia fracture model (TFM) was developed to study CRPS pathogenesis. This comprehensive review summarizes the published TFM research and compares these experimental results with the CRPS literature. The TFM generated spontaneous and evoked pain behaviors, inflammatory symptoms (edema, warmth), and trophic changes (skin thickening, osteoporosis) resembling symptoms in early CRPS. Neuropeptides, inflammatory cytokines, and nerve growth factor (NGF) have been linked to pain behaviors, inflammation, and trophic changes in the TFM model and proliferating keratinocytes were identified as the primary source of cutaneous cytokines and NGF. Tibia fracture also activated spinal glia and upregulated spinal neuropeptide, cytokine, and NGF expression, and in the brain it changed dendritic architecture. B cell-expressed immunoglobulin M antibodies also contributed to pain behavior, indicating a role for adaptive immunity. These results modeled many findings in early CRPS, but significant differences were also noted.

      Perspective

      Multiple neuroimmune signaling mechanisms contribute to the pain, inflammation, and trophic changes observed in the injured limb of the rodent TFM. This model replicates many of the symptoms, signs, and pathophysiology of early CRPS, but most post-fracture changes resolve within 5 months and may not contribute to perpetuating chronic CRPS.

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