Department Human Neuroscience, Sapienza University, Rome, Italy.
Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Denmark.
Eur J Pain. 2018 Nov;22(10):1727-1734. doi: 10.1002/ejp.1259. Epub 2018 Jul 9.
Patients with diabetic polyneuropathy commonly suffer from ongoing burning pain and dynamic mechanical allodynia. In this clinical and skin biopsy study, we aimed at assessing how intraepidermal regenerating nerve sprouts are associated with these two types of pain.
We consecutively enrolled 85 patients with diabetic polyneuropathy. All patients underwent skin biopsy at the distal leg. Intraepidermal nerve fibres were immunostained with the anti-protein gene product 9.5 (PGP9.5) to quantify all intraepidermal nerve fibres, and the growth-associated protein 43 (GAP43) to quantify regenerating nerve sprouts.
We found that the GAP43-stained intraepidermal nerve fibre density and the ratio GAP43/PGP9.5 were significantly higher in patients with ongoing burning pain than in those without. The area of receiver operating characteristic (ROC) curve for the ratio GAP43/PGP9.5 was 0.74 and yielded a sensitivity and specificity for identifying ongoing burning pain of 72% and 71%, respectively. Conversely, although the density of PGP9.5 and GAP43 intraepidermal nerve fibre was higher in patients with dynamic mechanical allodynia than in those without, this difference was statistically weak and the ROC curve analysis of skin biopsy variables for this type of pain failed to reach the statistical significance.
Our clinical and skin biopsy study showed that ongoing burning pain was strongly associated with regenerating sprouts, as assessed with GAP43 immunostaining. This finding improves our understanding on the mechanisms underlying neuropathic pain in patients with diabetic polyneuropathy and suggests that the GAP43/PGP 9.5 ratio might be used as an objective marker for ongoing burning pain due to regenerating sprouts.
Our skin biopsy study showing that regenerating sprouts, as assessed with GAP43-staining, were strongly associated with ongoing burning pain, improves our knowledge on the mechanisms underlying neuropathic pain in patients with diabetes.
患有糖尿病性多发性神经病的患者常患有持续性灼痛和动态机械性痛觉过敏。在这项临床和皮肤活检研究中，我们旨在评估表皮内再生神经末梢与这两种类型的疼痛之间的关系。
我们连续招募了 85 名患有糖尿病性多发性神经病的患者。所有患者均在小腿远端进行皮肤活检。用抗蛋白基因产物 9.5（PGP9.5）对表皮内神经纤维进行免疫染色，以定量所有表皮内神经纤维，并使用生长相关蛋白 43（GAP43）定量再生神经末梢。
我们发现，持续性灼痛患者的 GAP43 染色表皮内神经纤维密度和 GAP43/PGP9.5 比值明显高于无持续性灼痛的患者。GAP43/PGP9.5 比值的受试者工作特征（ROC）曲线面积为 0.74，用于识别持续性灼痛的敏感性和特异性分别为 72%和 71%。相反，尽管动态机械性痛觉过敏患者的 PGP9.5 和 GAP43 表皮内神经纤维密度较高，但这种差异在统计学上较弱，并且皮肤活检变量的 ROC 曲线分析未能达到统计学意义。
我们的临床和皮肤活检研究表明，持续性灼痛与再生末梢强烈相关，这可以通过 GAP43 免疫染色来评估。这一发现加深了我们对糖尿病性多发性神经病患者神经病理性疼痛机制的理解，并表明 GAP43/PGP9.5 比值可能被用作由于再生末梢引起的持续性灼痛的客观标志物。
我们的皮肤活检研究表明，再生末梢与持续性灼痛强烈相关，这可以通过 GAP43 染色来评估，这一发现提高了我们对糖尿病患者神经病理性疼痛机制的认识。
