Nuffield Department of Clinical Neurosciences, The University of Oxford, Oxford, UK.
Department of Clinical Medicine, The Danish Pain Research Center, Aarhus, Denmark.
Brain. 2020 Jul 1;143(7):2009-2026. doi: 10.1093/brain/awaa163.
We only have a rudimentary understanding of the molecular and cellular determinants of nerve regeneration and neuropathic pain in humans. This cohort study uses the most common entrapment neuropathy (carpal tunnel syndrome) as a human model system to prospectively evaluate the cellular and molecular correlates of neural regeneration and its relationship with clinical recovery. In 60 patients undergoing carpal tunnel surgery [36 female, mean age 62.5 (standard deviation 12.2) years], we used quantitative sensory testing and nerve conduction studies to evaluate the function of large and small fibres before and 6 months after surgery. Clinical recovery was assessed with the global rating of change scale and Boston Carpal Tunnel Questionnaire. Twenty healthy participants provided normative data [14 female, mean age 58.0 (standard deviation 12.9) years]. At 6 months post-surgery, we noted significant recovery of median nerve neurophysiological parameters (P < 0.0001) and improvements in quantitative sensory testing measures of both small and large nerve fibre function (P < 0.002). Serial biopsies revealed a partial recovery of intraepidermal nerve fibre density [fibres/mm epidermis pre: 4.20 (2.83), post: 5.35 (3.34), P = 0.001], whose extent correlated with symptom improvement (r = 0.389, P = 0.001). In myelinated afferents, nodal length increased postoperatively [pre: 2.03 (0.82), post: 3.03 (1.23), P < 0.0001] suggesting that this is an adaptive phenomenon. Transcriptional profiling of the skin revealed 31 differentially expressed genes following decompression, with ADCYAP1 (encoding pituitary adenylate cyclase activating peptide, PACAP) being the most strongly upregulated (log2 fold-change 1.87, P = 0.0001) and its expression was associated with recovery of intraepidermal nerve fibres. We found that human induced pluripotent stem cell-derived sensory neurons expressed the receptor for PACAP and that this peptide could significantly enhance axon outgrowth in a dose-dependent manner in vitro [neurite length PACAP 1065.0 µm (285.5), vehicle 570.9 μm (181.8), P = 0.003]. In conclusion, carpal tunnel release is associated with significant cutaneous reinnervation, which correlates with the degree of functional improvement and is associated with a transcriptional programme relating to morphogenesis and inflammatory processes. The most highly dysregulated gene ADCYAP1 (encoding PACAP) was associated with reinnervation and, given that this peptide signals through G-protein coupled receptors, this signalling pathway provides an interesting therapeutic target for human sensory nerve regeneration.
我们对人类神经再生和神经病理性疼痛的分子和细胞决定因素只有初步的了解。本队列研究以最常见的嵌压性神经病（腕管综合征）为人类模型系统，前瞻性评估神经再生的细胞和分子相关性及其与临床恢复的关系。在 60 例接受腕管手术的患者[36 例女性，平均年龄 62.5（标准差 12.2）岁]中，我们使用定量感觉测试和神经传导研究在手术前和手术后 6 个月评估大纤维和小纤维的功能。临床恢复情况采用全球变化量表和波士顿腕管问卷进行评估。20 名健康参与者提供了正常数据[14 名女性，平均年龄 58.0（标准差 12.9）岁]。术后 6 个月，我们观察到正中神经神经生理参数有显著恢复（P<0.0001），小纤维和大纤维功能的定量感觉测试指标也有改善（P<0.002）。连续活检显示表皮内神经纤维密度部分恢复[纤维/mm 表皮前：4.20（2.83），后：5.35（3.34），P=0.001]，其程度与症状改善相关（r=0.389，P=0.001）。在有髓鞘传入纤维中，节后纤维长度术后增加[前：2.03（0.82），后：3.03（1.23），P<0.0001]，提示这是一种适应性现象。皮肤的转录谱分析显示，减压后有 31 个差异表达的基因，其中 ADCYAP1（编码垂体腺苷酸环化酶激活肽，PACAP）的上调最为显著（log2 倍数变化 1.87，P=0.0001），其表达与表皮内神经纤维的恢复有关。我们发现人类诱导多能干细胞衍生的感觉神经元表达 PACAP 的受体，这种肽可以在体外以剂量依赖性方式显著促进轴突生长[神经突长度 PACAP 1065.0 µm（285.5），载体 570.9 µm（181.8），P=0.003]。总之，腕管松解术与显著的皮肤再支配有关，这与功能改善的程度相关，并与涉及形态发生和炎症过程的转录程序相关。上调最显著的基因 ADCYAP1（编码 PACAP）与再支配有关，由于该肽通过 G 蛋白偶联受体信号传递，因此该信号通路为人类感觉神经再生提供了一个有趣的治疗靶点。
