title: Riluzole attenuates neuropathic pain and enhances functional recovery in a rodent model of cervical spondylotic myelopathy.
abstract: Cervical spondylotic myelopathy (CSM) is the commonest cause of spinal cord impairment worldwide and despite surgical treatment, it is commonly associated with chronic neuropathic pain and neurological impairment. Based on data suggesting a key role of sodium and glutamate mediated cellular injury in models of spinal cord compression, we examined whether riluzole, a sodium channel/glutamate blocker, could improve neurobehavioral outcomes in a rat model of CSM. To produce chronic progressive compression of the cervical spinal cord, we used an established model of graded mechanical cord compromise developed in our laboratory. The chronic (8weeks) mechanical compression of the cervical spinal cord resulted in persistent mechanical allodynia and thermal hyperalgesia at 8weeks. Moreover, we found increased expression of phosphorylated NR1 and NR2B in the dorsal horns as well as astrogliosis and increased microglia expression in the dorsal horns after mechanical compression. Following daily systemic administration for 7weeks after the induction of compression, riluzole (8mg/kg) significantly attenuated forelimb and hindlimb mechanical allodynia and alleviated thermal hyperalgesia in the tail. Importantly, riluzole led to a decrease in swing phase duration, an increase in hind leg swing speed and an increase paw intensity in gait analysis. Riluzole also decreased the number of phosphorylated NR1 and phosphorylated NR2B positive cells in the dorsal horns and the microglia activation in the dorsal horns. Together, our results indicate that systemic riluzole administration during chronic cervical spinal cord compression is effective at protecting spinal cord tissue, preserving neurobehavioral function and alleviating neuropathic pain, possibly by decreasing NMDA receptor phosphorylation in astrocytes and by eliminating microglia activation. As such, riluzole represents a promising clinical treatment for CSM.
authors.affiliation: Division of Genetics & Development, Toronto Western Research Institute, and Spinal Program, Krembil Neuroscience Centre, University Health Network, Toronto, Ontario M5T 2S8, Canada; Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun Su
authors.initials: ES
authors.lastname: Moon
authors.affiliation: Division of Genetics & Development, Toronto Western Research Institute, and Spinal Program, Krembil Neuroscience Centre, University Health Network, Toronto, Ontario M5T 2S8, Canada; Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Ontario, Canada.
authors.forename: Spyridon K
authors.initials: SK
authors.lastname: Karadimas
authors.affiliation: Division of Genetics & Development, Toronto Western Research Institute, and Spinal Program, Krembil Neuroscience Centre, University Health Network, Toronto, Ontario M5T 2S8, Canada.
authors.forename: Wen-Ru
authors.initials: WR
authors.lastname: Yu
authors.affiliation: Division of Genetics & Development, Toronto Western Research Institute, and Spinal Program, Krembil Neuroscience Centre, University Health Network, Toronto, Ontario M5T 2S8, Canada; Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Ontario, Canada.
authors.forename: James W
authors.initials: JW
authors.lastname: Austin
authors.affiliation: Division of Genetics & Development, Toronto Western Research Institute, and Spinal Program, Krembil Neuroscience Centre, University Health Network, Toronto, Ontario M5T 2S8, Canada; Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Ontario, Canada; Neuroscience Program, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Department of Surgery, Division of Neurosurgery, University of Toronto, Toronto, Ontario M5T 2S8, Canada. Electronic address: Michael.Fehlings@uhn.on.ca.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Fehlings
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005260:Female; D005684:Gait / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy; D009437:Neuralgia / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D020127:Recovery of Function; D019782:Riluzole / Q000627:therapeutic use*; D013118:Spinal Cord Diseases / Q000188:drug therapy / Q000378:metabolism; D055009:Spondylosis / Q000188:drug therapy*
chemical_list: D018691:Excitatory Amino Acid Antagonists; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D019782:Riluzole
keywords: CSM; Cervical spondylotic myelopathy; Drug treatment; Neuropathic pain; Riluzole; Rodent model; Spinal cord; Spine