Ranolazine attenuates mechanical allodynia associated with demyelination injury

Harry J. Gould, R. Denis Soignier, Sung R. Cho, Christian Hernandez, Ivan Diamond, Bradley K. Taylor, Dennis Paul

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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 (300-350g), 1μg/30μL 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, 50mg/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 30mg/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.

Original languageEnglish (US)
Pages (from-to)1771-1780
Number of pages10
JournalPain Medicine (United States)
Volume15
Issue number10
DOIs
StatePublished - Oct 1 2014

Keywords

  • Allodynia
  • Doxorubicin
  • Pain
  • Ranolazine

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