Institute of Neuroscience, Fourth Military Medical University, Xi'an 710032, PR China.
Brain. 2012 Feb;135(Pt 2):359-75. doi: 10.1093/brain/awr345. Epub 2012 Jan 23.
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, α-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.
痛性糖尿病周围神经病是糖尿病的常见并发症，可影响生活的多个方面，严重限制患者的日常功能。痛性糖尿病周围神经病的信号被认为起源于周围神经系统。然而，其外周性痛觉过敏的机制仍难以捉摸。大量研究表明，多模式伤害性 C 纤维在疼痛信号的产生和传导中起着关键作用，其损伤或炎症后的敏化导致明显的痛觉过敏。传统上，伤害性初级传入纤维的放电次数被认为是在游离神经末梢决定的，而无髓 C 纤维的延伸主轴仅涉及到放电序列可靠而忠实的传递到中枢末端。我们通过显示多模式伤害性 C 纤维的主轴在响应重复活动时可能无法发生动作电位的传导，从而挑战了这一经典观点。对传导失败的定量分析表明，传导失败的程度显示出频率依赖性。在 C 纤维的主轴上局部给予低阈值、快速激活钾电流阻断剂 α-树突毒素（0.5 nM）和持续钠电流阻断剂小剂量河豚毒素（<100 nM）可以相互调节传导失败的程度，证实传导失败确实发生在多模式伤害性 C 纤维的主轴上。在链脲佐菌素诱导的糖尿病后，一部分多模式伤害性 C 纤维对阈上机械刺激表现出高频放电，约占测试的多模式伤害性 C 纤维总数的三分之一。这些糖尿病大鼠中的高频放电多模式伤害性 C 纤维表现出明显减少的传导失败。在 C 纤维的主轴上给予低浓度的河豚毒素和 Nav1.8 选择性阻断剂 A-803467，发现其在糖尿病大鼠中以剂量依赖性方式显著增强传导失败。糖尿病大鼠小背根神经节神经元和周围 C 纤维中钠通道亚基 Nav1.7 和 Nav1.8 的表达上调，以及小背根神经节神经元中的瞬时和持续钠电流增加和兴奋性增强，可能是糖尿病高频放电多模式伤害性 C 纤维传导失败减少的基础。这项研究为多模式伤害性 C 纤维的主轴在疼痛信号处理中的功能能力提供了新的认识，并揭示了糖尿病性痛觉过敏的新机制。
