Reversal of thermal and mechanical allodynia with pregabalin in a mouse model of oxaliplatin-induced peripheral neuropathy

Abstract

Abstract Aims Chemotherapy-induced peripheral neuropathy (CIPN) is a dose limiting side effect in the use of the platinum-based antineoplastic drug oxaliplatin as a treatment for colorectal cancer. Currently there is no treatment available to reverse the neurotoxicity which presents as pain, sensory loss and cold allodynia in up to 80% of patients. The aim of this study is to investigate if pregabalin can reverse the allodynia caused by oxaliplatin in CIPN. Methods CIPN was induced in 10 male C57BL/6 mice (6 weeks-old) with a single intraperitoneal injection of oxaliplatin (15 mg/kg i.p.). Signs of thermal and mechanical allodynia were assessed from baseline to 20 days after injection by Cold/Hot plate (Bioseb, France) at 20 °C and hand-held von Frey (vF) hairs of gradually increasing weights. Pregabalin (3 mg/kg and 10 mg/kg p.o.) was administered to treat CIPN. Results Mechanical and thermal allodynia were established 3 days post-oxaliplatin injection and remained stable for 14 days. At day 15, pregabalin (3 mg/kg p.o.) reversed mechanical allodynia to baseline scores at 2 h (H) post-dosing and thermal allodynia at 1 and 2H post-dosing. Following a 2-day wash out where scores returned to neuropathic baseline, pregabalin (10 mg/kg p.o.) reverted scores for mechanical and thermal allodynia to baseline scores at both 1 and 2H. Thermal testing was performed either immediately after vF or alone and our results were similar, showing no iatrogenic effects of vF on thermal sensitivity. Correlation analysis of the responses to thermal and mechanical stimuli showed no significant trend, indicating that oxaliplatin-induced peripheral neuropathy affects the mechanical and thermal modalities in different ways. Conclusion Oxaliplatin-induced peripheral neuropathy as measured by thermal and mechanical allodynia is reversible by a single dose of pregabalin. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 642720. RM is funded by a Marie Sklodowska-Curie grant agreement No. 642720 doing a joint PhD with the Royal Veterinary Collage and Transpharmation Ltd. AF and NU are employees of Transpharmation Ltd.