title: Ranolazine attenuates mechanical allodynia associated with demyelination injury.
abstract: OBJECTIVE
  The aim of this study was to determine whether ranolazine, a new medication that targets sodium channels to improve cardiac ischemia and angina, could be an effective analgesic agent for pain associated with demyelination injury.
  
  
  BACKGROUND
  Many agents have been used to treat neuropathic pain but not all neuropathic conditions respond similarly to treatment. We have demonstrated that ranolazine, an agent that blocks voltage-gated sodium channels Nav 1.4, 1.5, 1.7, and 1.8, is effective in attenuating mechanical hyperalgesia in both complete Freund's adjuvant and spared nerve injury preclinical models of inflammatory and neuropathic pain, respectively. Here we test the efficacy of this drug in a newly validated model of demyelination injury that responds uniquely to a number of treatment options.
  
  
  METHODS
  After determination of baseline nerve conduction velocities (NCVs) and withdrawal responses from heat and mechanical stimulation in male Sprague-Dawley rats (300-350 g), 1 μg/30 μL of doxorubicin was injected into one sciatic nerve. The contralateral nerve provided a sham-injected control. Two weeks after doxorubicin injection, NCV and sensitivity to heat and mechanical stimulation were reassessed before and after treatment with ranolazine (10, 30, 50 mg/kg) administered intraperitoneally using an experimenter-blinded, randomized design.
  
  
  RESULTS
  Doxorubicin injection produced a significant hyperalgesic effect in response to mechanical but not heat stimulation. Conduction velocities in the injected limbs were reduced when compared with controls. Ranolazine reduced mechanical allodynia with peak efficacy at 30 mg/kg. Fifty milligram/kilogram ranolazine restored NCVs by approximately 50%, but had no effect in the uninjected limb.
  
  
  CONCLUSIONS
  Ranolazine exerts broad-spectrum actions to reduce mechanical allodynia that is associated with peripheral demyelination injury.
authors.affiliation: Department of Physical Medicine and Rehabilitation, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA; Department of Neurology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA; Department of Pain Mastery Center of Louisiana, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Harry J
authors.initials: HJ
authors.lastname: Gould
authors.forename: R Denis
authors.initials: RD
authors.lastname: Soignier
authors.forename: Sung R
authors.initials: SR
authors.lastname: Cho
authors.forename: Christian
authors.initials: C
authors.lastname: Hernandez
authors.forename: Ivan
authors.initials: I
authors.lastname: Diamond
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Taylor
authors.forename: Dennis
authors.initials: D
authors.lastname: Paul
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000818:Animals; D003711:Demyelinating Diseases / Q000150:complications / Q000473:pathology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D009437:Neuralgia / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology*; D000069458:Ranolazine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000293:injuries
chemical_list: D000083:Acetanilides; D004791:Enzyme Inhibitors; D010879:Piperazines; D000069458:Ranolazine
keywords: Allodynia; Doxorubicin; Pain; Ranolazine