An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Na(v)1.6 in peripheral pain pathways

Cold allodynia, pain in response to cooling, occurs during or within hours of oxaliplatin infusion and is thought to arise from a direct effect of oxaliplatin on peripheral sensory neurons. To characterize the pathophysiological mechanisms underlying acute oxaliplatin-induced cold allodynia, we established a new intraplantar oxaliplatin mouse model that rapidly developed long-lasting cold allodynia mediated entirely through tetrodotoxin-sensitive Na-v pathways. Using selective inhibitors and knockout animals, we found that Na(v)1.6 was the key isoform involved, while thermosensitive transient receptor potential channels were not involved. Consistent with a crucial role for delayed-rectifier potassium channels in excitability in response to cold, intraplantar administration of the K+-channel blocker 4-aminopyridine mimicked oxaliplatin-induced cold allodynia and was also inhibited by Na(v)1.6 blockers. Intraplantar injection of the Na(v)1.6 activator Cn2 elicited spontaneous pain, mechanical allodynia, and enhanced 4-aminopyridine-induced cold allodynia. These findings provide behavioural evidence for a crucial role of Na(v)1.6 in multiple peripheral pain pathways including cold allodynia. (c) 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved