Institute of Clinical Pharmacology, Goethe-University, Frankfurt, Germany.
Department of Dermatology, Venerology, and Allergology, University Hospital Frankfurt, Frankfurt, Germany.
Pain. 2019 Dec;160(12):2699-2709. doi: 10.1097/j.pain.0000000000001660.
Human cold perception and nociception play an important role in persisting pain. However, species differences in the target temperature of thermosensitive ion channels expressed in peripheral nerve endings have fueled discussions about the mechanism of cold nociception in humans. Most frequently implicated thermosensors are members of the transient receptor potential (TRP) ion channel family TRPM8 and TRPA1. Regularly observed, distinct cold pain phenotype groups suggested the existence of interindividually differing molecular bases. In 28 subjects displaying either high or medium sensitivity to local cooling of the skin, the density at epidermal nerve fibers of TRPM8, but not that of TRPA1 expression, correlated significantly with the cold pain threshold. Moreover, reproducible grouping of the subjects, based on high or medium sensitivity to cooling, was reflected in an analogous grouping based on high or low TRPM8 expression at epidermal nerve fibers. The distribution of TRPM8 expression in epidermal nerve fibers provided an explanation for the previously observed (bi)modal distribution of human cold pain thresholds which was reproduced in this study. In the light of current controversies on the role of human TRPA1 ion channels in cold pain perception, the present observations demonstrating a lack of association of TRPA1 channel expression with cold sensitivity-related measures reinforce doubts about involvement of this channel in cold pain in humans. Since TRP inhibitors targeting TRPM8 and TRPA1 are currently entering clinical phases of drug development, the existence of known species differences, in particular in the function of TRPA1, emphasizes the increasing importance of new methods to directly approach the roles of TRPs in humans.
人类对寒冷的感知和伤害感受在持续性疼痛中起着重要作用。然而，外周神经末梢表达的热敏离子通道的目标温度在物种间存在差异，这引发了关于人类冷伤害感受机制的讨论。最常涉及的热敏传感器是瞬时受体电位 (TRP) 离子通道家族 TRPM8 和 TRPA1 的成员。经常观察到，不同的冷痛表型群体表明存在个体间不同的分子基础。在 28 名对皮肤局部冷却表现出高或中等敏感性的受试者中，表皮神经纤维中 TRPM8 的密度，但不是 TRPA1 的表达，与冷痛阈值显著相关。此外，基于对冷却的高或中等敏感性对受试者进行可重复分组，反映在基于表皮神经纤维中 TRPM8 高或低表达的类似分组中。表皮神经纤维中 TRPM8 的表达分布为之前观察到的人类冷痛阈值的（双）模态分布提供了解释，本研究重现了这一分布。鉴于当前关于人类 TRPA1 离子通道在冷痛感知中的作用的争议，本研究观察到 TRPA1 通道表达与冷敏感性相关测量之间缺乏关联，这进一步加强了对该通道参与人类冷痛的怀疑。由于靶向 TRPM8 和 TRPA1 的 TRP 抑制剂目前正在进入药物开发的临床阶段，已知物种差异的存在，特别是 TRPA1 的功能，强调了需要新方法来直接研究 TRP 在人类中的作用的重要性。
