title: Cell cycle inhibition limits development and maintenance of neuropathic pain following spinal cord injury.
abstract: 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.
authors.affiliation: Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, MD, USA Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA Department of Pain and Translational Symptom Science, University of Maryland School of Nursing, Baltimore, MD, USA.
authors.forename: Junfang
authors.initials: J
authors.lastname: Wu
authors.forename: Zaorui
authors.initials: Z
authors.lastname: Zhao
authors.forename: Xiya
authors.initials: X
authors.lastname: Zhu
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Renn
authors.forename: Susan G
authors.initials: SG
authors.lastname: Dorsey
authors.forename: Alan I
authors.initials: AI
authors.lastname: Faden
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D005149:Facial Expression; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009437:Neuralgia / Q000209:etiology*; D010147:Pain Measurement; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D013119:Spinal Cord Injuries / Q000150:complications* / Q000473:pathology; D018709:Statistics, Nonparametric
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D005419:Flavonoids; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C077990:alvocidib