Department of Neurobiology and Department of Anesthesiology of First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
Sci Transl Med. 2022 Apr 6;14(639):eabh2557. doi: 10.1126/scitranslmed.abh2557.
Diabetic neuropathic pain (DNP) is a common and devastating complication in patients with diabetes. The mechanisms mediating DNP are not completely elucidated, and effective treatments are lacking. A-fiber sensory neurons have been shown to mediate the development of mechanical allodynia in neuropathic pain, yet the molecular basis underlying the contribution of A-fiber neurons is still unclear. Here, we report that the orphan G protein-coupled receptor 177 (GPR177) in A-fiber neurons drives DNP via WNT5a-mediated activation of transient receptor potential vanilloid receptor-1 (TRPV1) ion channel. GPR177 is mainly expressed in large-diameter A-fiber dorsal root ganglion (DRG) neurons and required for the development of DNP in mice. Mechanistically, we found that GPR177 mediated the secretion of WNT5a from A-fiber DRG neurons into cerebrospinal fluid (CSF), which was necessary for the maintenance of DNP. Extracellular perfusion of WNT5a induced rapid currents in both TRPV1-expressing heterologous cells and nociceptive DRG neurons. Computer simulations revealed that WNT5a has the potential to bind the residues at the extracellular S5-S6 loop of TRPV1. Using a peptide able to disrupt the predicted WNT5a/TRPV1 interaction suppressed DNP- and WNT5a-induced neuropathic pain symptoms in rodents. We confirmed coexpression in human DRG neurons and WNT5A secretion in CSF from patients with DNP. Thus, our results reveal a role for WNT5a as an endogenous and potent TRPV1 agonist, and the GPR177-WNT5a-TRPV1 axis as a driver of DNP pathogenesis in rodents. Our findings identified a potential analgesic target that might relieve neuropathic pain in patients with diabetes.
糖尿病性神经病理性疼痛（DNP）是糖尿病患者常见且严重的并发症。介导 DNP 的机制尚未完全阐明，且缺乏有效的治疗方法。有研究表明，A 纤维感觉神经元介导神经病理性疼痛中机械性痛觉过敏的发展，然而，A 纤维神经元贡献的分子基础仍不清楚。在这里，我们报告在 A 纤维神经元中，孤儿 G 蛋白偶联受体 177（GPR177）通过 WNT5a 介导的瞬时受体电位香草酸受体 1（TRPV1）离子通道的激活来驱动 DNP。GPR177 主要表达在大直径 A 纤维背根神经节（DRG）神经元中，并且是小鼠 DNP 发展所必需的。从机制上讲，我们发现 GPR177 介导 A 纤维 DRG 神经元中的 WNT5a 分泌到脑脊液（CSF）中，这对于 DNP 的维持是必需的。WNT5a 的细胞外灌流会在表达 TRPV1 的异源细胞和伤害感受性 DRG 神经元中诱导快速电流。计算机模拟表明，WNT5a 有可能与 TRPV1 的细胞外 S5-S6 环上的残基结合。使用能够破坏预测的 WNT5a/TRPV1 相互作用的肽可抑制 DNP 和 WNT5a 诱导的啮齿动物神经病理性疼痛症状。我们在人类 DRG 神经元中证实了共表达，并在 DNP 患者的 CSF 中证实了 WNT5A 的分泌。因此，我们的研究结果揭示了 WNT5a 作为一种内源性、有效 TRPV1 激动剂的作用，以及 GPR177-WNT5a-TRPV1 轴作为啮齿动物 DNP 发病机制的驱动因素。我们的发现确定了一个潜在的镇痛靶点，可能会缓解糖尿病患者的神经病理性疼痛。
