Increased peptidergic fibers as a potential cutaneous marker of pain in diabetic small fiber neuropathy
Increased peptidergic fibers as a potential cutaneous marker of pain in diabetic small fiber neuropathy
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DOI：
10.1097/j.pain.0000000000002054
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发表时间：
2021-03-01
期刊：
影响因子：
7.4
通讯作者：
Nolano, Maria
中科院分区：
文献类型：
--
作者：
Karlsson, Pall;Provitera, Vincenzo;Nolano, Maria
糖尿病性多发性神经病（DPN）是糖尿病的常见并发症，常伴有神经性疼痛。疼痛性DPN的发生和维持机制在很大程度上是未知的，皮肤活检的表皮内神经纤维密度的定量是诊断DPN的神经病理学金标准之一，不能区分有疼痛和无疼痛的患者。识别疼痛性DPN患者可能的疼痛病理生理学生物标志物可能会增加我们对神经病理性疼痛机制的认识。疼痛性DPN的动物模型显示肽能神经纤维（P物质和降钙素基因相关肽）密度增加。在这项研究中，我们对一组特征明确的DPN患者进行了详细的皮肤活检分析，主要是小纤维受累，伴或不伴疼痛，并在健康对照组中进行了皮肤活检结果与疼痛强度和定量感觉测试之间的相关性测试。我们发现，虽然有和没有疼痛的患者之间的蛋白质基因产物9.5的表皮内神经纤维密度没有差异，疼痛患者的真皮肽能纤维含有P物质和降钙素基因相关肽的密度增加与无痛DPN患者和健康对照。肽能神经纤维密度与疼痛患者的疼痛等级相关（R = 0.33; P = 0.019），但与定量感觉测试结果无关。在这篇文章中，我们首次在人类中发现，疼痛性DPN中真皮肽能纤维密度增加。这些发现为糖尿病疼痛的病理生理机制提供了新的见解，并为新的治疗靶点的研究开辟了道路。
Diabetic polyneuropathy (DPN) is a common complication of diabetes and is often associated with neuropathic pain. The mechanisms underlying development and maintenance of painful DPN are largely unknown, and quantification of intraepidermal nerve fiber density from skin biopsy, one of the neuropathological gold standard when diagnosing DPN, does not differentiate between patients with and without pain. Identification of possible pain pathophysiological biomarkers in patients with painful DPN may increase our knowledge of mechanisms behind neuropathic pain. Animal models of painful DPN have been shown to have an increased density of peptidergic nerve fibers (substance P and calcitonin gene-related peptide). In this study, we performed a detailed skin biopsy analysis in a well-characterized group of DPN patients with primarily small fiber involvement, with and without pain, and in healthy controls and test for correlation between skin biopsy findings and pain intensity and quantitative sensory testing. We found that although there was no difference in intraepidermal nerve fiber density using protein gene product 9.5 between patients with and without pain, patients with pain had increased density of dermal peptidergic fibers containing substance P and calcitonin gene-related peptide compared with patients with painless DPN and healthy controls. Peptidergic nerve fiber density correlated with pain ratings in patients with pain (R = 0.33; P = 0.019), but not with quantitative sensory testing results. In this article, we show, for the first time in humans, an increased density of dermal peptidergic fibers in painful DPN. These findings provide new insight in the pathophysiological mechanisms of pain in diabetes and open the research towards new therapeutic targets.