Reduced conduction failure of the main axon of polymodal nociceptive C-fibres contributes to painful diabetic neuropathy in rats
Reduced conduction failure of the main axon of polymodal nociceptive C-fibres contributes to painful diabetic neuropathy in rats
复制标题
多模式伤害性 C 纤维主轴突传导衰竭减少导致大鼠疼痛性糖尿病神经病变
DOI：
10.1093/brain/awr345
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发表时间：
2012-02-01
期刊：
影响因子：
14.5
通讯作者：
Hu, San-Jue
中科院分区：
文献类型：
--
作者：
Sun, Wei;Miao, Bei;Hu, San-Jue
痛性糖尿病神经病变是糖尿病的常见并发症，可影响生活的方方面面，严重限制患者的日常生活功能。痛性糖尿病神经病变的信号被认为起源于周围神经系统。然而，其痛觉过敏的外围机制仍然难以捉摸。大量研究表明，多通道伤害性C纤维在痛觉信号的产生和传导以及损伤或炎症后的敏化导致明显的痛觉过敏中起着至关重要的作用。传统上，伤害性初级传入放电的数量被认为是在自由神经末梢决定的，而无髓C纤维的延伸主轴只涉及到可靠和忠实的放电序列向中枢终末的传播。我们挑战了这一经典观点，证明了当动作电位沿着多模式伤害性感受性C纤维的主轴行进时，动作电位的传导可能无法响应重复的活动。对传导失效的定量分析表明，传导失效的程度具有频率依赖性。在C纤维主轴上局部应用低阈值、快速激活的钾电流阻断剂、α-树突状毒素(0.5 NM)和持续性钠电流阻滞剂，小剂量河豚毒素(<；100 NM)可相互调节传导障碍的程度，证实多模式伤害性感受性C纤维主轴确实存在传导障碍。在链脲佐菌素诱导的糖尿病后，一组多通道伤害性C纤维表现出高放电频率到阈值以上的机械刺激，约占所测试的多通道伤害性C纤维总数的三分之一。这些高放电频率的多模式伤害性C纤维在糖尿病大鼠身上显示出显著减少传导失败的作用。在糖尿病大鼠C纤维主轴突上注射低浓度河豚毒素和NAV1.8选择性阻滞剂A-803467可显著增强糖尿病大鼠的传导失败，并呈剂量依赖关系。糖尿病大鼠背根神经节小神经元和外周C纤维钠通道亚单位Nav1.7和Nav1.8的表达上调，以及糖尿病大鼠小背根神经节神经元瞬时和持续钠电流的增强以及兴奋性的增强，可能是糖尿病大鼠高放电频率多模式伤害性感受性C纤维传导失败减少的基础。本研究揭示了多模式伤害性C纤维主轴在痛觉信号处理中的功能，揭示了糖尿病痛觉过敏的新机制。
Painful diabetic neuropathy is a common complication of diabetes mellitus and can affect many aspects of life and severely limit patients' daily functions. Signals of painful diabetic neuropathy are believed to originate in the peripheral nervous system. However, its peripheral mechanism of hyperalgesia has remained elusive. Numerous studies have accumulated that polymodal nociceptive C-fibres play a crucial role in the generation and conduction of pain signals and sensitization of which following injury or inflammation leads to marked hyperalgesia. Traditionally, the number of nociceptive primary afferent firings is believed to be determined at the free nerve endings, while the extended main axon of unmyelinated C-fibres only involves the reliable and faithful propagation of firing series to the central terminals. We challenged this classic view by showing that conduction of action potential can fail to occur in response to repetitive activity when they travel down the main axon of polymodal nociceptive C-fibres. Quantitative analysis of conduction failure revealed that the degree of conduction failure displays a frequency-dependent manner. Local administration of low threshold, rapidly activating potassium current blocker, alpha-dendrotoxin (0.5 nM) and persistent sodium current blocker, low doses of tetrodotoxin (< 100 nM) on the main axon of C-fibres can reciprocally regulate the degree of conduction failure, confirming that conduction failure did occur along the main axon of polymodal nociceptive C-fibres. Following streptozotocin-induced diabetes, a subset of polymodal nociceptive C-fibres exhibited high-firing-frequency to suprathreshold mechanical stimulation, which account for about one-third of the whole population of polymodal nociceptive C-fibres tested. These high-firing-frequency polymodal nociceptive C-fibres in rats with diabetes displayed a marked reduction of conduction failure. Delivery of low concentrations of tetrodotoxin and Nav1.8 selective blocker, A-803467 on the main axon of C-fibres was found to markedly enhance the conduction failure in a dose-dependent manner in diabetic rats. Upregulated expression of sodium channel subunits Nav1.7 and Nav1.8 in both small dorsal root ganglion neurons and peripheral C-fibres as well as enhanced transient and persistent sodium current and increased excitability in small dorsal root ganglion neurons from diabetic rats might underlie the reduced conduction failure in the diabetic high-firing-frequency polymodal nociceptive C-fibres. This study shed new light on the functional capability in the pain signals processing for the main axon of polymodal nociceptive C-fibres and revealed a novel mechanism underlying diabetic hyperalgesia.