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  3. A model of neuropathic pain induced by sorafenib in the rat: Effect of dimiracetam

A model of neuropathic pain induced by sorafenib in the rat: Effect of dimiracetam

  • Neurotoxicology. 2015 Sep;50:101-7. doi: 10.1016/j.neuro.2015.08.002.
Lorenzo Di Cesare Mannelli 1,  Mario Maresca 2,  Carlo Farina 3,  Michael W Scherz 4,  Carla Ghelardini 2
Affiliations

Affiliations

  • 1 Department of Neuroscience, Psychology, Drug Research and Child Health, - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Viale G. Pieraccini, 6, 50139 Firenze, Italy. Electronic address: [email protected].
  • 2 Department of Neuroscience, Psychology, Drug Research and Child Health, - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Viale G. Pieraccini, 6, 50139 Firenze, Italy.
  • 3 Neurotune AG, Wagistrasse 27a, CH-8952 Schlieren, Switzerland; Metys Pharmaceuticals, Friedrichstrasse 6, CH-4055 Basel, Switzerland.
  • 4 Metys Pharmaceuticals, Friedrichstrasse 6, CH-4055 Basel, Switzerland.
PMID: 26254739 DOI: 10.1016/j.neuro.2015.08.002
Abstract

Background: Sorafenib is a kinase inhibitor Anticancer drug whose repeated administration causes the onset of a peripheral painful neuropathy. Notably, the efficacy of common analgesic drugs is not adequate and this often leads pre-mature discontinuation of Anticancer therapy. The aim of this study was to establish a rat model of sorafenib-induced neuropathic pain, and to assess the effect of the new anti-neuropathic compound dimiracetam in comparison with gabapentin, pregabalin and duloxetine.

Methods: Male Sprague-Dawley rats were treated i.v. (10 mg kg(-1)), i.p. (10 and 30 mg kg(-1)) or p.o. (80 and 160 mg kg(-1)) with sorafenib once daily for 21 days. Pain behaviour measurements (cold plate, paw pressure, electronic von Frey) were performed on days 0, 7, 14 and 21.

Results: Sorafenib lowered the paw-licking threshold to non-noxious cold stimuli on day 14 of all protocols evaluated. The i.p. administration resulted in greater efficacy than the other administration routes. Sorafenib treatments did not affect paw-withdrawal responses to non-noxious or to noxious mechanical stimuli. On day 14, dimiracetam (300 mg kg(-1)), gabapentin (100 mg kg(-1)), pregabalin (30 mg kg(-1)) and duloxetine (30 mg kg(-1)) were acutely administered p.o. in sorafenib i.p.-treated rats. A single oral dose of dimiracetam induced a statistically significant increase of the pain threshold 15 min after administration. Pregabalin induced a comparable effect, whereas gabapentin and duloxetine were ineffective. Repeated twice-daily administration of dimiracetam (150 mg kg(-1) p.o.), starting on the first day of i.p sorafenib administration, significantly protected rats from sorafenib-induced decrease in the paw-licking threshold.

Conclusions: A rat model of sorafenib-induced hypersensitivity to cold stimulation has been established. Dimiracetam and pregabalin are effective in prevention of sorafenib-induced neuropathy in this model.

Keywords

Chemotherapy-induced neuropathy; Dimiracetam; Neuropathic pain; Pain model; Pregabalin; Sorafenib.

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