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

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.

• Authors: Lorenzo Di Cesare Mannelli, Mario Maresca, Carlo Farina, Michael W Scherz, Carla Ghelardini
• Journal: Neurotoxicology (Neurotoxicology) Vol. 50 Pg. 101-7 (Sep 2015) ISSN: 1872-9711 [Electronic] Netherlands
• PMID: 26254739 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Analgesics
• Antineoplastic Agents
• Imidazoles
• Phenylurea Compounds
• Pyrroles
• Niacinamide
• dimiracetam
• Sorafenib

Topics

• Analgesics (therapeutic use)
• Analysis of Variance
• Animals
• Antineoplastic Agents (toxicity)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Hyperalgesia (drug therapy)
• Imidazoles (therapeutic use)
• Male
• Neuralgia (chemically induced)
• Niacinamide (analogs & derivatives, toxicity)
• Pain Measurement
• Pain Threshold (drug effects)
• Phenylurea Compounds (toxicity)
• Pyrroles (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Reaction Time (drug effects)
• Sorafenib
• Time Factors