title: Riluzole effects on behavioral sensitivity and the development of axonal damage and spinal modifications that occur after painful nerve root compression.
abstract: OBJECTIVE
  Cervical radiculopathy is often attributed to cervical nerve root injury, which induces extensive degeneration and reduced axonal flow in primary afferents. Riluzole inhibits neuro-excitotoxicity in animal models of neural injury. The authors undertook this study to evaluate the antinociceptive and neuroprotective properties of riluzole in a rat model of painful nerve root compression.
  
  
  METHODS
  A single dose of riluzole (3 mg/kg) was administered intraperitoneally at Day 1 after a painful nerve root injury. Mechanical allodynia and thermal hyperalgesia were evaluated for 7 days after injury. At Day 7, the spinal cord at the C-7 level and the adjacent nerve roots were harvested from a subgroup of rats for immunohistochemical evaluation. Nerve roots were labeled for NF200, CGRP, and IB4 to assess the morphology of myelinated, peptidergic, and nonpeptidergic axons, respectively. Spinal cord sections were labeled for the neuropeptide CGRP and the glutamate transporter GLT-1 to evaluate their expression in the dorsal horn. In a separate group of rats, electrophysiological recordings were made in the dorsal horn. Evoked action potentials were identified by recording extracellular potentials while applying mechanical stimuli to the forepaw.
  
  
  RESULTS
  Even though riluzole was administered after the onset of behavioral sensitivity at Day 1, its administration resulted in immediate resolution of mechanical allodynia and thermal hyperalgesia (p < 0.045), and these effects were maintained for the study duration. At Day 7, axons labeled for NF200, CGRP, and IB4 in the compressed roots of animals that received riluzole treatment exhibited fewer axonal swellings than those from untreated animals. Riluzole also mitigated changes in the spinal distribution of CGRP and GLT-1 expression that is induced by a painful root compression, returning the spinal expression of both to sham levels. Riluzole also reduced neuronal excitability in the dorsal horn that normally develops by Day 7. The frequency of neuronal firing significantly increased (p < 0.045) after painful root compression, but riluzole treatment maintained neuronal firing at sham levels.
  
  
  CONCLUSIONS
  These findings suggest that early administration of riluzole is sufficient to mitigate nerve root-mediated pain by preventing development of neuronal dysfunction in the nerve root and the spinal cord.
authors.affiliation: Departments of Bioengineering and.
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Nicholson
authors.forename: Sijia
authors.initials: S
authors.lastname: Zhang
authors.forename: Taylor M
authors.initials: TM
authors.lastname: Gilliland
authors.forename: Beth A
authors.initials: BA
authors.lastname: Winkelstein
mesh_terms: D000818:Animals; D001369:Axons; D006930:Hyperalgesia / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D019838:Neck Injuries / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D019547:Neck Pain / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D009408:Nerve Compression Syndromes / Q000150:complications*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011843:Radiculopathy / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019782:Riluzole / Q000494:pharmacology*; D013126:Spinal Nerve Roots / Q000293:injuries*
chemical_list: D018696:Neuroprotective Agents; D019782:Riluzole
keywords: CGRP = calcitonin gene–related peptide; GLT-1; HSD = honestly significant difference; IB4 = isolectin-B4; LTM = low-threshold mechanoreceptive; NF200 = neurofilament-200; ROI = region of interest; WDR = wide dynamic range; injury; nerve root; neuronal hyperexcitability; pain; radiculopathy; riluzole; spinal cord injury