title: 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.affiliation: 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: lorenzo.mannelli@unifi.it.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Viale G. Pieraccini, 6, 50139 Firenze, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Maresca
authors.affiliation: Neurotune AG, Wagistrasse 27a, CH-8952 Schlieren, Switzerland; Metys Pharmaceuticals, Friedrichstrasse 6, CH-4055 Basel, Switzerland.
authors.forename: Carlo
authors.initials: C
authors.lastname: Farina
authors.affiliation: Metys Pharmaceuticals, Friedrichstrasse 6, CH-4055 Basel, Switzerland.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Scherz
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health, - Neurofarba - Pharmacology and Toxicology Section, University of Florence, Viale G. Pieraccini, 6, 50139 Firenze, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D009437:Neuralgia / Q000139:chemically induced*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000633:toxicity; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010671:Phenylurea Compounds / Q000633:toxicity*; D011758:Pyrroles / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D000077157:Sorafenib; D013997:Time Factors
chemical_list: D000700:Analgesics; D000970:Antineoplastic Agents; D007093:Imidazoles; D010671:Phenylurea Compounds; D011758:Pyrroles; D009536:Niacinamide; C085079:dimiracetam; D000077157:Sorafenib
keywords: Chemotherapy-induced neuropathy; Dimiracetam; Neuropathic pain; Pain model; Pregabalin; Sorafenib