Evidence for the involvement of peripheral cold-sensitive TRPM8 channels in human cutaneous hygrosensation

Abstract

In contrast to other species, humans are believed to lack hygroreceptors for sensing skin wetness. Yet, the molecular basis of human hygrosensation is currently unknown, and it remains unclear whether we possess a receptor-mediated sensing mechanism for skin wetness. The aim of this study was to assess the role of the cutaneous cold-sensitive transient receptor potential melastatin-8 (TRPM8) channel as a molecular mediator of human hygrosensation. To this end, we exploited both the thermal and chemical activation of TRPM8-expressing cutaneous Aδ cold thermoreceptors, and we assessed wetness sensing in healthy young men in response to 1) dry skin cooling in the TRPM8 range of thermosensitivity and 2) application of the TRPM8 agonist menthol. Our results indicate that 1) independently of contact with moisture, a cold-dry stimulus in the TRPM8 range of activation induced wetness perceptions across 12 different body regions and those wetness perceptions varied across the body following regional differences in cold sensitivity; and 2) independently of skin cooling, menthol-induced stimulation of TRPM8 triggered wetness perceptions that were greater than those induced by physical dry cooling and by contact with an aqueous cream containing actual moisture. For the first time, we show that the cutaneous cold-sensing TRPM8 channel plays the dual role of cold and wetness sensor in human skin and that this ion channel is a peripheral mediator of human skin wetness perception.

TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation

“…The involvement of the TRPM8 channels as a molecular mediator of human hygrosensation was also recently described [111], with a cold-dry stimulus inducing wellness perception, as it performed the activation by the TRPM8 agonist menthol (1), independently of the concurrence of a cooling stimulus or not. TRPM8 channels have also been found at the surface of immune system T-cells, and their activation with the agonist WS-12 (3, Figure 1) resulted in T-cell stimulation, with an increase in CD25 and CD69 levels [112].…”

Skin wetness detection thresholds and wetness magnitude estimations of the human index fingerpad and their modulation by moisture temperature

“…This shows that there must be other factors involved in wetness perception and supports previous mechanistic work. For example, cold cues have been associated with wetness in the absence of physical wetness, when using a nerve block ( 25 ) and in the absence of physical skin cooling ( 26 ). As visual and auditory cues were removed or controlled in the present study, this brings a focus back on to the roles of haptics.…”

Nutritional Regulation of Human Brown Adipose Tissue

“…Menthol is a compound found in mint and is an activator of the calcium-permeable cation channel, transient receptor potential melastatin 8 (TRPM8) [ 139 , 140 ]. TRMP8 is expressed in sensory nerves in the skin, senses cold temperature and functions as a ligand-gated channel to menthol, inducing a cold sensation [ 141 ]. TRPM8 is expressed in murine BAT and activation by menthol increases BAT Ucp1 mRNA and protein expression [ 142 ].…”