Reducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy
Reducing CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic neuropathy
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DOI：
10.1172/jci92117
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发表时间：
2018-06-01
影响因子：
15.9
通讯作者：
Menichella, Daniela M.
中科院分区：
文献类型：
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作者：
Jayaraj, Nirupa D.;Bhattacharyya, Bula J.;Menichella, Daniela M.
疼痛性糖尿病神经病变（PDN）是糖尿病的一种难治性并发症，影响25%的患者。PDN以神经性疼痛和小纤维变性为特征，伴有背根神经节（DRG）伤害感受器的高兴奋性和皮肤内轴突的丧失。PDN中DRG伤害感受器高兴奋性和小纤维变性的分子机制尚不清楚。我们假设趋化因子CXCL12/CXCR4信号传导是这一机制的核心，因为我们已经证明CXCL12/CXCR4信号传导对于机械性异常性疼痛的发展是必要的，这是PDN中常见的疼痛超敏行为。以表达钠通道Na(v)1.8的DRG神经元为研究对象，我们应用转基因、电生理、成像和化学发生技术来验证这一假设。在高脂饮食小鼠PDN模型中，我们能够通过限制CXCR4信号传导或神经元兴奋性来预防和逆转机械性异常痛和小纤维变性。本研究揭示Na(v)1.8阳性DRG神经元中的兴奋性CXCR4/CXCL12信号在PDN小鼠模型的机械异常性痛和小纤维变性的发病机制中起关键作用。因此，我们提出靶向cxcr4介导的DRG伤害感受器高兴奋性是一种很有希望的治疗方法，可以改善这种目前难治性和广泛的疾病。
Painful diabetic neuropathy (PDN) is an intractable complication of diabetes that affects 25% of patients. PDN is characterized by neuropathic pain and small-fiber degeneration, accompanied by dorsal root ganglion (DRG) nociceptor hyperexcitability and loss of their axons within the skin. The molecular mechanisms underlying DRG nociceptor hyperexcitability and small-fiber degeneration in PDN are unknown. We hypothesize that chemokine CXCL12/CXCR4 signaling is central to this mechanism, as we have shown that CXCL12/CXCR4 signaling is necessary for the development of mechanical allodynia, a pain hypersensitivity behavior common in PDN. Focusing on DRG neurons expressing the sodium channel Na(v)1.8, we applied transgenic, electrophysiological, imaging, and chemogenetic techniques to test this hypothesis. In the high-fat diet mouse model of PDN, we were able to prevent and reverse mechanical allodynia and small-fiber degeneration by limiting CXCR4 signaling or neuronal excitability. This study reveals that excitatory CXCR4/CXCL12 signaling in Na(v)1.8-positive DRG neurons plays a critical role in the pathogenesis of mechanical allodynia and small-fiber degeneration in a mouse model of PDN. Hence, we propose that targeting CXCR4-mediated DRG nociceptor hyperexcitability is a promising therapeutic approach for disease-modifying treatments for this currently intractable and widespread affliction.