Department of Medical Neurobiology, Faculty of Medicine and the Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew University, Jerusalem, Israel.
Pediatric Neurology Unit, Pediatric Department, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel.
J Clin Invest. 2023 Feb 1;133(3):e153558. doi: 10.1172/JCI153558.
BACKGROUNDChronic pain is a debilitating illness with currently limited therapy, in part due to difficulties in translating treatments derived from animal models to patients. The transient receptor potential vanilloid 1 (TRPV1) channel is associated with noxious heat detection and inflammatory pain, and reports of adverse effects in human trials have hindered extensive efforts in the clinical development of TRPV1 antagonists as novel pain relievers.METHODSWe examined 2 affected individuals (A1 and A2) carrying a homozygous missense mutation in TRPV1, rendering the channel nonfunctional. Biochemical and functional assays were used to analyze the mutant channel. To identify possible phenotypes of the affected individuals, we performed psychophysical and medical examinations.RESULTSWe demonstrated that diverse TRPV1 activators, acting at different sites of the channel protein, were unable to open the cloned mutant channel. This finding was not a consequence of impairment in the expression, cellular trafficking, or assembly of protein subunits. The affected individuals were insensitive to application of capsaicin to the mouth and skin and did not demonstrate aversive behavior toward capsaicin. Furthermore, quantitative sensory testing of A1 revealed an elevated heat-pain threshold but also, surprisingly, an elevated cold-pain threshold and extensive neurogenic inflammatory, flare, and pain responses following application of the TRPA1 channel activator mustard oil.CONCLUSIONOur study provides direct evidence in humans for pain-related functional changes linked to TRPV1, which is a prime target in the development of pain relievers.FUNDINGSupported by the Israel Science Foundation (368/19); Teva's National Network of Excellence in Neuroscience grant (no. 0394886) and Teva's National Network of Excellence in Neuroscience postdoctoral fellowship.
慢性疼痛是一种使人虚弱的疾病，目前的治疗方法有限，部分原因是将动物模型中的治疗方法转化为患者治疗存在困难。瞬时受体电位香草酸 1 型（TRPV1）通道与有害热探测和炎症性疼痛有关，并且在人体试验中报告的不良反应阻碍了 TRPV1 拮抗剂作为新型止痛药的广泛临床开发。
我们检查了携带 TRPV1 纯合错义突变的 2 名受影响个体（A1 和 A2），使通道失去功能。使用生化和功能测定来分析突变通道。为了确定受影响个体的可能表型，我们进行了心理物理和医学检查。
我们证明了多种 TRPV1 激活剂，作用于通道蛋白的不同部位，无法打开克隆的突变通道。这一发现不是由于表达、细胞运输或蛋白亚基组装受损所致。受影响的个体对口腔和皮肤应用辣椒素无反应，并且对辣椒素没有表现出厌恶行为。此外，对 A1 进行的定量感觉测试显示，热痛阈值升高，但令人惊讶的是，冷痛阈值升高，并且在应用 TRPA1 通道激活剂芥末油后，出现广泛的神经源性炎症、 flare 和疼痛反应。
我们的研究为 TRPV1 相关的人类疼痛相关功能变化提供了直接证据，TRPV1 是开发止痛药的主要靶点。
由以色列科学基金会（368/19）资助；Teva 的国家神经科学卓越网络拨款（编号 0394886）和 Teva 的国家神经科学卓越网络博士后奖学金。
