Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy
Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy
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DOI：
10.1038/nm.2750
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发表时间：
2012-06-01
期刊：
影响因子：
82.9
通讯作者：
Nawroth, Peter P.
中科院分区：
文献类型：
--
作者：
Bierhaus, Angelika;Fleming, Thomas;Nawroth, Peter P.
本研究建立了一个基于糖酵解代谢产物甲基乙二醛的代谢性痛觉过敏的机制。我们发现，血浆丙酮醛浓度高于600 nM区分糖尿病患者疼痛和那些没有疼痛。甲基乙二醛使感觉神经元去极化，并诱导电压门控钠通道Na（v）1.8的翻译后修饰，这与伤害性神经元的电兴奋性增加和易化放电有关，而它促进Na（v）1.7的缓慢失活。在小鼠中，甲基乙二醛治疗降低神经传导速度，促进降钙素基因相关肽的神经分泌，增加环氧合酶-2（考克斯-2）表达，并引起热和机械性痛觉过敏。这种痛觉过敏通过参与疼痛处理的大脑区域的血流量增加来反映。我们在链脲佐菌素诱导的糖尿病小鼠模型和遗传性糖尿病小鼠模型中也发现了类似的变化，但在Na（v）1.8敲除（Scn 10（-/-））小鼠中没有发现。包括甲基乙二醛清除剂在内的几种策略在减少甲基乙二醛和糖尿病诱导的痛觉过敏中是有效的。代谢驱动的痛觉过敏这一先前未描述的概念为疼痛性糖尿病神经病变的治疗干预设计提供了新的基础。
This study establishes a mechanism for metabolic hyperalgesia based on the glycolytic metabolite methylglyoxal. We found that concentrations of plasma methylglyoxal above 600 nM discriminate between diabetes-affected individuals with pain and those without pain. Methylglyoxal depolarizes sensory neurons and induces post-translational modifications of the voltage-gated sodium channel Na(v)1.8, which are associated with increased electrical excitability and facilitated firing of nociceptive neurons, whereas it promotes the slow inactivation of Na(v)1.7. In mice, treatment with methylglyoxal reduces nerve conduction velocity, facilitates neurosecretion of calcitonin gene-related peptide, increases cyclooxygenase-2 (COX-2) expression and evokes thermal and mechanical hyperalgesia. This hyperalgesia is reflected by increased blood flow in brain regions that are involved in pain processing. We also found similar changes in streptozotocin-induced and genetic mouse models of diabetes but not in Na(v)1.8 knockout (Scn10(-/-)) mice. Several strategies that include a methylglyoxal scavenger are effective in reducing methylglyoxal-and diabetes-induced hyperalgesia. This previously undescribed concept of metabolically driven hyperalgesia provides a new basis for the design of therapeutic interventions for painful diabetic neuropathy.