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

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• 作者：Jennifer R. Deuis ; Katharina Zimmermann ; Andrej A. Romanovsky ; Lourival D. Possani ; Peter J. Cabot ; Richard J. Lewis ; Irina Vetter
• 关键词：Voltage-gated sodium channel ; Allodynia
• 刊名：Pain
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：154
• 期：9
• 页码：1749-1757
• 全文大小：995 K

文摘

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.