Ralfinamide administered orally before hindpaw neurectomy or postoperatively provided long-lasting suppression of spontaneous neuropathic pain-related behavior in the rat

Zhang, Shi-Hong; Blech-Hermoni, Yotam; Faravelli, Laura; Seltzer, Ze’ev

doi:10.1016/j.pain.2008.04.020

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Volume 139, Issue 2 , Pages 293-305, 15 October 2008

Ralfinamide administered orally before hindpaw neurectomy or postoperatively provided long-lasting suppression of spontaneous neuropathic pain-related behavior in the rat

Shi-Hong Zhang
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, PR China
- Centre for the Study of Pain, Faculties of Dentistry and Medicine, University of Toronto, 124 Edward Street, Toronto, Ont., Canada M5G 1G6
Yotam Blech-Hermoni
- Centre for the Study of Pain, Faculties of Dentistry and Medicine, University of Toronto, 124 Edward Street, Toronto, Ont., Canada M5G 1G6
- National Human Genome Research Institute, NIH, Bethesda, MD, USA
Laura Faravelli
- Discovery Department, Newron Pharmaceuticals SpA, Bresso (MI), Italy
Ze’ev Seltzer
- Centre for the Study of Pain, Faculties of Dentistry and Medicine, University of Toronto, 124 Edward Street, Toronto, Ont., Canada M5G 1G6
- Corresponding author. Tel.: +1 416 979 4900x4433; fax: +1 416 979 4936.

Received 29 June 2007; received in revised form 18 April 2008; accepted 24 April 2008. published online 26 June 2008.

Abstract

Ralfinamide is analgesic when applied as a single dose in rodent models of stimulus-evoked chronic pain. However, it is unknown whether its chronic application after nerve injury can suppress spontaneous chronic pain, the main symptom driving patients to seek treatment. In this study ralfinamide was administered to rats at doses producing plasma levels similar to those causing analgesia in pain patients. The analgesic effect was tested on autotomy, a behavior of self-mutilation of a denervated paw that models spontaneous neuropathic pain. Sprague–Dawley male rats (N=10–20/group) underwent transection of the sciatic and saphenous nerves unilaterally. Ralfinamide or its vehicle were administered per os for 7 days preoperatively (80mg/kg; bid), followed by the vehicle or Ralfinamide, until postoperative d42. Autotomy was scored daily until d63. Lasting ‘preemptive analgesia’ was found in rats treated with ralfinamide preoperatively, expressed by delayed autotomy onset (P=0.009) and reduced scores on d63 (P=0.01). Rats treated with ralfinamide (30 or 60mg/kg; bid) from the operation till d42, but not preoperatively, also showed delayed autotomy (P=0.05, P=0.006), and reduced autotomy scores lasting till d63 (P=0.02, P=0.01), for the two doses, respectively. Combining ralfinamide treatments for 7 days preoperatively and 42 days postoperatively also resulted in significantly suppressed scores on d42 and d63 (P=0.005, P=0.001, respectively). Suppression of neuropathic pain-related behavior was likely caused by a combination of mechanisms reported for ralfinamide, including inhibition of Na⁺ and Ca⁺⁺ currents in Nav1.3, Nav1.7, Nav1.8, and Cav2.2 channels in rat DRG neurons, inhibition of substance P release from spinal cord synaptosomes, NMDA receptor antagonism and neuroprotection.