Ranolazine produces its anti-anginal effects by blocking the late sodium current associated with the voltage-gated sodium channel, Nav 1.5. In addition, ranolazine use-dependently inhibits Nav 1.7 and 1.8, sodium channels linked to the regulation of inflammatory and/or neuropathic pain. Therefore, we used a preclinical model of neuropathic pain to evaluate the anti-allodynic and anti-hyperalgesic potential of ranolazine. Male, Sprague-Dawley rats (∼250g) were used in accordance with regulations of the Tulane IACUC. The tibial and common peroneal nerves were transected, sparing the sural branch of the sciatic nerve. Both before and 1-2 wk after spared nerve injury, we assessed tactile threshold with von Frey filaments (up-down method) and cold hypersensitivity with topical acetone. Ranolazine (10, 30, 100 mg/kg) was dissolved in dichloromethane and propylene glycol (i.p.) or water (pH 4.0, p.o.). Drug or vehicle was administered using an experimenter-blinded, randomized design. Behavioral assessment occurred at 15, 30, 60, and 90 min (i.p.) or 30, 60, 90, 120, and 180 min (p.o.) after administration. The ability of animals to remain on an accelerating rotarod was assessed before and after i.p. administration of vehicle or ranolazine. Intraperitoneal ranolazine, but not vehicle, dose-dependently reduced mechanical and cold allodynia, with a peak effect at 15-30 min and a duration of less than 90 min. Oral ranolazine produced similar results, with a peak effect at 90 min and a duration of less than 180 minutes. Ranolazine only produced ataxia at the highest dose of 100mg/kg i.p. We conclude that systemic administration of ranolazine inhibits neuropathic pain in rats at doses that do not produce ataxia or other behavioral side effects. Clinical investigation of ranolazine for the treatment of neuropathic pain is warranted. Ranolazine produces its anti-anginal effects by blocking the late sodium current associated with the voltage-gated sodium channel, Nav 1.5. In addition, ranolazine use-dependently inhibits Nav 1.7 and 1.8, sodium channels linked to the regulation of inflammatory and/or neuropathic pain. Therefore, we used a preclinical model of neuropathic pain to evaluate the anti-allodynic and anti-hyperalgesic potential of ranolazine. Male, Sprague-Dawley rats (∼250g) were used in accordance with regulations of the Tulane IACUC. The tibial and common peroneal nerves were transected, sparing the sural branch of the sciatic nerve. Both before and 1-2 wk after spared nerve injury, we assessed tactile threshold with von Frey filaments (up-down method) and cold hypersensitivity with topical acetone. Ranolazine (10, 30, 100 mg/kg) was dissolved in dichloromethane and propylene glycol (i.p.) or water (pH 4.0, p.o.). Drug or vehicle was administered using an experimenter-blinded, randomized design. Behavioral assessment occurred at 15, 30, 60, and 90 min (i.p.) or 30, 60, 90, 120, and 180 min (p.o.) after administration. The ability of animals to remain on an accelerating rotarod was assessed before and after i.p. administration of vehicle or ranolazine. Intraperitoneal ranolazine, but not vehicle, dose-dependently reduced mechanical and cold allodynia, with a peak effect at 15-30 min and a duration of less than 90 min. Oral ranolazine produced similar results, with a peak effect at 90 min and a duration of less than 180 minutes. Ranolazine only produced ataxia at the highest dose of 100mg/kg i.p. We conclude that systemic administration of ranolazine inhibits neuropathic pain in rats at doses that do not produce ataxia or other behavioral side effects. Clinical investigation of ranolazine for the treatment of neuropathic pain is warranted.