Topical Menthol Application Augments Cutaneous Microvascular Blood Flow

Abstract

Menthol, the active ingredient in several topical analgesic gels, activates transient receptor potential melastatin 8 (TRPM8) receptors on sensory nerves, eliciting a cold sensation and potentially vasoconstriction. Menthol can also act on vascular TRPM8 receptors inducing vasodilation. PURPOSE: We sought to characterize the cutaneous vascular effects of topical menthol application and to determine the mechanism(s) through which menthol may alter skin blood flow (SkBF). METHODS: Three distinct protocols were conducted in three groups of 10 young (24±1 years), healthy subjects in a double blind placebo control design. Red cell flux was measured via laser speckle contrast imaging (Moor FLPI) in all protocols and normalized to cutaneous vascular conductance (CVC=flux*mmHg-1). Protocol 1: Placebo and 4% menthol gels were applied separately to 60cm2 of skin without local thermal control and SkBF was continuously measured. Protocol 2: Seven concentrations of menthol gel (0.04%, 0.4%, 1%, 2%, 4%, 7%, 8%) were applied to the skin to model the dose-response relation. Protocol 3: Both with and without pretreatment with topical lidocaine, placebo and 4% menthol gels were applied to skin under local thermal control (33°C). Post-occlusive reactive hyperemia (PORH) and local heating (42°C) protocols were conducted to determine the contribution of endothelium derived hyperpolarizing factors (EDHFs) and nitric oxide, respectively. Data were expressed as CVC for all protocols. RESULTS: Topical menthol application increased SkBF compared to placebo (3.4±0.3 v 1.1±0.2 CVC: p<0.001). During the dose response, SkBF increased with increasing doses of menthol (main effect, p<0.05) with an ED50 of 1%. Similarly, SkBF was augmented with menthol application during PORH (3.6±0.3 v 2.5±0.2 CVC; p<0.001), but not local heating (3.0±0.2 v 2.9±0.3 CVC; p=0.44). Concurrent sensory nerve inhibition attenuated menthol-mediated dilation at thermoneutral baseline (1.3±0.2 CVC; p<0.001) and during PORH (2.8±0.3 CVC; p<0.001), but not during local heating (3.4±0.2 CVC; p=0.1). CONCLUSION: Topically applied menthol dose-dependently increases blood flow in the cutaneous microvasculature. This increase in blood flow is mediated, in-part by EDHFs and sensory nerves.