• Junfang Wu, Zaorui Zhao, Xiya Zhu, Cynthia L Renn, Susan G Dorsey, and Alan I Faden.
• aDepartment of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD, USA bDepartment of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA cDepartment of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore, MD, USA.
• Pain. 2016 Feb 1; 157 (2): 488-503.

AbstractChronic pain after spinal cord injury (SCI) may present as hyperalgesia, allodynia, and/or spontaneous pain and is often resistant to conventional pain medications. Identifying more effective interventions to manage SCI pain requires improved understanding of the pathophysiological mechanisms involved. Cell cycle activation (CCA) has been implicated as a key pathophysiological event following SCI. We have shown that early central or systemic administration of a cell cycle inhibitor reduces CCA, prevents glial changes, and limits SCI-induced hyperesthesia. Here, we compared the effects of early vs late treatment with the pan-cyclin-dependent kinase inhibitor flavopiridol on allodynia as well as spontaneous pain. Adult C57BL/6 male mice subjected to moderate SCI were treated with intraperitoneal injections of flavopiridol (1 mg/kg), daily for 7 days beginning either 3 hours or 5 weeks after injury. Mechanical/thermal allodynia was evaluated, as well as spontaneous pain using the mouse grimace scale (MGS). We show that sensitivity to mechanical and thermal stimulation, and locomotor dysfunction were significantly reduced by early flavopiridol treatment compared with vehicle-treated controls. Spinal cord injury caused robust and extended increases of MGS up to 3 weeks after trauma. Early administration of flavopiridol significantly shortened duration of MGS changes. Late flavopiridol intervention significantly limited hyperesthesia at 7 days after treatment, associated with reduced glial changes, but without effect on locomotion. Thus, our data suggest that cell cycle modulation may provide an effective therapeutic strategy to reduce hyperesthesia after SCI, with a prolonged therapeutic window.

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