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

•Sorafenib induces hypersensitivity to a cold non noxious stimulus in the rat.•Sorafenib i.p. administration is more efficient than p.o., s.c. and e.v. routes.•Dimiracetam and pregabalin are effective against sorafenib-induced pain in the rat. 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. Male Sprague-Dawley rats were treated i.v. (10mgkg−1), i.p. (10 and 30mgkg−1) or p.o. (80 and 160mgkg−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. 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 (300mgkg−1), gabapentin (100mgkg−1), pregabalin (30mgkg−1) and duloxetine (30mgkg−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 15min after administration. Pregabalin induced a comparable effect, whereas gabapentin and duloxetine were ineffective. Repeated twice-daily administration of dimiracetam (150mg 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. 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.