title: Cell cycle activation contributes to increased neuronal activity in the posterior thalamic nucleus and associated chronic hyperesthesia after rat spinal cord contusion.
abstract: Spinal cord injury (SCI) causes not only sensorimotor and cognitive deficits, but frequently also severe chronic pain that is difficult to treat (SCI pain). We previously showed that hyperesthesia, as well as spontaneous pain induced by electrolytic lesions in the rat spinothalamic tract, is associated with increased spontaneous and sensory-evoked activity in the posterior thalamic nucleus (PO). We have also demonstrated that rodent impact SCI increases cell cycle activation (CCA) in the injury region and that post-traumatic treatment with cyclin dependent kinase inhibitors reduces lesion volume and motor dysfunction. Here we examined whether CCA contributes to neuronal hyperexcitability of PO and hyperpathia after rat contusion SCI, as well as to microglial and astroglial activation (gliopathy) that has been implicated in delayed SCI pain. Trauma caused enhanced pain sensitivity, which developed weeks after injury and was correlated with increased PO neuronal activity. Increased CCA was found at the thoracic spinal lesion site, the lumbar dorsal horn, and the PO. Increased microglial activation and cysteine-cysteine chemokine ligand 21 expression was also observed in the PO after SCI. In vitro, neurons co-cultured with activated microglia showed up-regulation of cyclin D1 and cysteine-cysteine chemokine ligand 21 expression. In vivo, post-injury treatment with a selective cyclin dependent kinase inhibitor (CR8) significantly reduced cell cycle protein induction, microglial activation, and neuronal activity in the PO nucleus, as well as limiting chronic SCI-induced hyperpathia. These results suggest a mechanistic role for CCA in the development of SCI pain, through effects mediated in part by the PO nucleus. Moreover, cell cycle modulation may provide an effective therapeutic strategy to improve reduce both hyperpathia and motor dysfunction after SCI.
authors.affiliation: Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research, National Study Center for Trauma and EMS, University of Maryland, School of Medicine, Bressler Research Building, 655 W. Baltimore Street, Room #6-009, Baltimore, MD 21201, USA. jwu@anes.umm.edu
authors.forename: Junfang
authors.initials: J
authors.lastname: Wu
authors.forename: Charles
authors.initials: C
authors.lastname: Raver
authors.forename: Chunshu
authors.initials: C
authors.lastname: Piao
authors.forename: Asaf
authors.initials: A
authors.lastname: Keller
authors.forename: Alan I
authors.initials: AI
authors.lastname: Faden
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016213:Cyclins / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005500:Follow-Up Studies; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000188:drug therapy / Q000209:etiology; D006941:Hyperesthesia / Q000209:etiology* / Q000473:pathology*; D008297:Male; D017628:Microglia / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D036421:Nerve Fibers, Unmyelinated / Q000473:pathology; D009474:Neurons / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D020656:Posterior Thalamic Nuclei / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D013997:Time Factors
chemical_list: D016213:Cyclins; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein