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Cell cycle inhibition limits development and maintenance of neuropathic pain following spinal cord injury

Wu, Junfang; Zhao, Zaorui; Zhu, Xiya; Renn, Cynthia L.; Dorsey, Susan G.; Faden, Alan I.

doi: 10.1097/j.pain.0000000000000393
Research Paper

Chronic 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.

Spinal cord injury causes spontaneous pain and hyperesthesia. Cell cycle inhibition limits such changes, possibly by limiting microglial/astrocyte activation.

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

Corresponding author. Address: Department of Anesthesiology, Anatomy and Neurobiology, Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Tel.: +1 410 706 5189; fax: +1 410 706 1751. E-mail address: jwu@anes.umm.edu (J. Wu).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received August 04, 2015

Received in revised form October 01, 2015

Accepted October 14, 2015

© 2016 International Association for the Study of Pain
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