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Cell Cycle Activation Contributes to Increased Neuronal Activity in the Posterior Thalamic Nucleus and Associated Chronic Hyperesthesia after Rat Spinal Cord Contusion

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Neurotherapeutics

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.

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Acknowledgments

This study was supported by the National Institutes of Health Grants R01 NS054221 (AIF) and R01 NS066965 (AK). We thank Michael Dinizo, Kelsey Guanciale, Rainier Cabatbat, Katherine Cardiff, Marie Hanscom, Angela Pan, and Aicha Moutanni for expert technical support.

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The authors declare that they have no competing financial interests.

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Authors and Affiliations

  1. Department of Anesthesiology & Center for Shock, Trauma and Anesthesiology Research (STAR), 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

    Junfang Wu, Chunshu Piao & Alan I. Faden

  2. Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA

    Charles Raver & Asaf Keller

  3. Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA

    Asaf Keller & Alan I. Faden

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  1. Junfang Wu
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Correspondence to Junfang Wu.

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Junfang Wu and Charles Raver contributed equally to this article.

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Wu, J., Raver, C., Piao, C. et al. Cell Cycle Activation Contributes to Increased Neuronal Activity in the Posterior Thalamic Nucleus and Associated Chronic Hyperesthesia after Rat Spinal Cord Contusion. Neurotherapeutics 10, 520–538 (2013). https://doi.org/10.1007/s13311-013-0198-1

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