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Ranolazine Attenuation of CFA-induced Mechanical Hyperalgesia

Authors

  • Gregory P. Casey BS,

    1. Departments of Cell Biology and Anatomy,
    2. Pain Mastery Center of Louisiana, Louisiana State University Health Sciences Center, New Orleans, Louisiana;
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  • Jomar S. Roberts MD,

    1. Neurology, and
    2. Pain Mastery Center of Louisiana, Louisiana State University Health Sciences Center, New Orleans, Louisiana;
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  • Dennis Paul PhD,

    1. Pharmacology and
    2. Pain Mastery Center of Louisiana, Louisiana State University Health Sciences Center, New Orleans, Louisiana;
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  • Ivan Diamond MD, PhD,

    1. Gilead Sciences Inc., Palo Alto, California, USA
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  • Harry J. Gould III MD, PhD

    Corresponding author
    1. Neurology, and
    2. Pain Mastery Center of Louisiana, Louisiana State University Health Sciences Center, New Orleans, Louisiana;
      Harry J. Gould III, MD, PhD, Department of Neurology, 533 Bolivar Street, LSU Health Sciences Center, New Orleans, LA 70112, USA. Tel: 504-568-4090; Fax: 504-568-7130; E-mail: hgould@lsuhsc.edu.
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Harry J. Gould III, MD, PhD, Department of Neurology, 533 Bolivar Street, LSU Health Sciences Center, New Orleans, LA 70112, USA. Tel: 504-568-4090; Fax: 504-568-7130; E-mail: hgould@lsuhsc.edu.

Abstract

Objective.  To determine whether ranolazine, a new anti-angina medication, could be an effective analgesic agent in complete Freund's adjuvant-induced inflammatory pain.

Background.  Plantar injection of complete Freund's adjuvant (CFA) produces an extended period of hyperalgesia that is associated with a dramatic up-regulation of Nav 1.7 sodium channels in populations of large and small dorsal root ganglion neurons related to the injection site. Ranolazine appears to produce its anti-angina effect through blocking the late sodium current associated with the voltage-gated sodium channel, Nav 1.5. Because ranolazine also inhibits Nav 1.7, and 1.8, we sought to determine whether it could be an effective analgesic agent in CFA-induced inflammatory pain.

Methods.  Baseline determinations of withdrawal from thermal and mechanical stimulation were made in Sprague-Dawley rats (∼300–350 × g). Following determination of baseline, one hindpaw in each group was injected with 0.1 mL of CFA. The contralateral paw received saline. Thermal and mechanical stimulation was repeated on the third day post-injection. Vehicle (0.9% isotonic saline; pH 3.0) or ranolazine was then administered in randomized and blinded doses either by intraperitoneal (ip) injection (0, 10, 20, and 50 mg/kg) or by oral gavage (po; 0, 20, 50, 100, and 200 mg/kg). Animals were again tested 30 minutes (ip) and 1 hour (po) after drug administration.

Results.  Ranolazine produced dose-dependant analgesia on mechanical allodynia induced by CFA injection, but had no effect on thermal hyperalgesia.

Conclusions.  Ranolazine's potential as a new option for managing both angina and chronic inflammatory pain warrants further study.

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