Epidermal Expression of TRPM8 But Not of TRPA1 Ion Channels is Associated with Human Cold Pain Sensitivity Patterns

Human cold perception and nociception play an important role in persisting pain. However, species differences in the target temperature of thermosensitive ion channels expressed at peripheral nerve endings have fueled discussions about the mechanism of cold nociception in humans. Most frequently implicated thermosensors are the members of the transient receptor potential (TRP) ion channel family TRPM8 and TRPA1. Reproducibly observed distinct cold pain phenotype groups hinted at inter individually differing molecular bases. In 28 subjects displaying either high or medium cold pain sensitivity, the density of TRPM8 but not that of TRPA1 expression at dermal nerve fibers correlated significantly with the cold pain threshold. Moreover, a reproducible grouping of the subjects based on high or medium cold pain sensitivity was reflected in an analogous grouping based on high or low TRPM8 expression at dermal nerve fibers. The distribution of TRPM8 expression in dermal nerve fibers provided a sufficient explanation of the previously observed and presently reproduced (bi)modal distribution of human cold pain thresholds. Considering current controversies about the role of human TRPA1 ion channels in cold pain perception, the present observations with a lack of association of TRPA1 channel expression with pain related measures fuels doubts about its involvement in cold pain in humans. Considering that TRP inhibitors targeting TRPM8 and TRPA1 are currently entering clinical phases of drug development, known species differences, in particular in the function of TRPA1, emphasize an increasing importance of research methods developed to approach TRPs directly in humans. Funding Statement: This work has been funded by the Else Kroner-Fresenius Foundation (EKFS), Research Training Group Translational Research Innovation – Pharma (TRIP, JL) and by the Landesoffensive zur Entwicklung wissenschaftlich - okonomischer Exzellenz (LOEWE), LOEWE-Zentrum fur Translationale Medizin und Pharmakologie (JL). Declaration of Interests: The authors have declared that no competing interests exist. Ethics Approval Statement: The study followed the Declaration of Helsinki and was approved by the Ethics Committee of the Medical Faculty of the Goethe – University Frankfurt am Main, Germany (protocol number 110/16).