Menthol-induced activation of TRPM8 receptors increases cutaneous blood flow across the dermatome.

Abstract

Topical menthol-based analgesics increase skin blood flow (SkBF) through transient receptor potential melastatin 8 (TRPM8) receptor-dependent activation of sensory nerves and endothelium-derived hyperpolarization factors. It is unclear if menthol-induced TRPM8 activation mediates a reflex change in SkBF across the dermatome in an area not directly treated with menthol. The purpose of this study was to determine the effects of localized topical menthol application on SkBF across a common dermatome. We hypothesized that SkBF would be increased with menthol at the site of application and across the dermatome (contralateral limb) through a spinal reflex mechanism. In a double blind, placebo controlled, cross-over design, 15 healthy participants (7 men; age=22±1yrs) were treated with direct application (3ml over 8×13cm) of 5% menthol gel (Biofreeze™) or placebo gel on the L4 dermatome, separated by 48h. Red blood cell flux was measured using laser Doppler flowmetry over the area of application, on the contralateral leg of the same dermatome, and in a separate dermatome (L5/S1) to serve as control. Cutaneous vascular conductance was calculated for each measurement site (CVC=flux/MAP). At baseline there were no differences in CVC between menthol and placebo gels, or among sites (all p>0.05). After 30±6min, CVC increased at the treated site with menthol (0.12±0.02 vs. 1.36±0.19flux/mmHg, p<0.01) but not the placebo (0.10±0.01 vs. 0.18±0.04flux/mmHg, p=0.91). There was a modest increase in CVC at the contralateral L4 dermatome with menthol gel (0.16±0.04 vs. 0.29±0.06flux/mmHg, p<0.01), but not placebo (0.11±0.02 vs. 0.15±0.03flux/mmHg, p=0.41). There was no effect on SkBF from either treatments at the L5/S1 control dermatome (both, p>0.05), suggesting the lack of a systemic response. In conclusion, menthol containing topical analgesic gels increased SkBF at the treated site, and modestly throughout the dermatome. These data suggest menthol-induced activation of the TRPM8 receptors induces an increase in SkBF across the area of common innervation through a localized spinal reflex mechanism.