An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Na_v1.6 in peripheral pain pathways

Abstract

Summary 

Cold allodynia elicited by local intraplantar injection of the chemotherapeutic agent oxaliplatin is mediated through Na_v1.6-expressing peripheral sensory fibres. Activation of Na_v1.6 alone elicits only mechanical allodynia and spontaneous pain, but when combined with inhibition of K_v channels, profound cold allodynia develops.

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_v1.6 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_v1.6 blockers. Intraplantar injection of the Na_v1.6 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_v1.6 in multiple peripheral pain pathways including cold allodynia.