An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1.6 in peripheral pain pathways.
An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1.6 in peripheral pain pathways.
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DOI：
10.1016/j.pain.2013.05.032
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发表时间：
2013-09
期刊：
影响因子：
7.4
通讯作者：
Vetter I
中科院分区：
文献类型：
--
作者：
Deuis JR;Zimmermann K;Romanovsky AA;Possani LD;Cabot PJ;Lewis RJ;Vetter I
冷异常性疼痛，即对冷却反应的疼痛，发生在奥沙利铂输注期间或输注后数小时内，被认为是由奥沙利铂对外周感觉神经元的直接作用引起的。为了表征急性奥沙利铂诱导的冷异常性疼痛的病理生理学机制，我们建立了一种新的足底奥沙利铂小鼠模型，该模型完全通过河豚毒素敏感性Nav通路介导快速发展长期冷异常性疼痛。使用选择性抑制剂和敲除动物，我们发现Nav1.6是参与的关键亚型，而热敏瞬时受体电位通道不参与。与延迟整流钾通道在响应寒冷的兴奋性中的关键作用一致，足底注射K+通道阻滞剂4-氨基吡啶模拟了奥沙利铂诱导的冷异常性疼痛，并且也被Navl.6阻滞剂抑制。足底注射Nav1.6激活剂Cn2引起自发性疼痛、机械性异常性疼痛和增强的4-氨基吡啶诱导的冷异常性疼痛。这些发现为Nav1.6在多个外周疼痛通路（包括冷异常性疼痛）中的关键作用提供了行为学证据。
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 Nav pathways. Using selective inhibitors and knockout animals, we found that Nav1.6 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 Navl.6 blockers. Intraplantar injection of the Nav1.6-activator Cn2 elicited spontaneous pain, mechanical allodynia and enhanced 4-aminopyridine-induced cold allodynia. These findings provide behavioural evidence for a crucial role of Nav1.6 in multiple peripheral pain pathways including cold allodynia.
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影响因子：
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