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Randomized Controlled Trial
. 2017 Mar:110:43-47.
doi: 10.1016/j.mvr.2016.11.008. Epub 2016 Nov 27.

Mechanisms and time course of menthol-induced cutaneous vasodilation

Daniel H Craighead  1 , Nathaniel B McCartney  2 , James H Tumlinson  2 , Lacy M Alexander  2
Affiliations
Randomized Controlled Trial

Mechanisms and time course of menthol-induced cutaneous vasodilation

Daniel H Craighead et al. Microvasc Res. 2017 Mar.

Abstract

Menthol is a vasoactive compound that is widely used in topical analgesic agents. Menthol induces cutaneous vasodilation, however the underlying mechanisms are unknown. Determining the rates of appearance and clearance of menthol in the skin is important for optimizing topical treatment formulation and dosing. The purpose of this study was to determine the mechanisms contributing to menthol-mediated cutaneous vasodilation and to establish a time course for menthol appearance/clearance in the skin. Ten young (23±1years, 5 males 5 females) subjects participated in two protocols. In study 1, four intradermal microdialysis fibers were perfused with increasing doses of menthol (0.1-500mM) and inhibitors for nitric oxide (NO), endothelium derived hyperpolarizing factors (EDHFs), and sensory nerves. Skin blood flow was measured with laser Doppler flowmetry and normalized to %CVCmax. In study 2, two intradermal microdialysis fibers were perfused with lactated Ringer's solution. 0.017mL·cm-2 of a 4% menthol gel was placed over each fiber. 5μL samples of dialysate from the microdialysis fibers were collected every 30min and analyzed for the presence of menthol with high performance gas chromatography/mass spectrometry. Skin blood flow (laser speckle contrast imaging) and subjective ratings of menthol sensation were simultaneously obtained with dialysate samples. In study 1, menthol induced cutaneous vasodilation at all doses ≥100mM (all p<0.05). However, inhibition of either NO, EDHFs, or sensory nerves fully inhibited menthol-mediated vasodilation (all p>0.05). In study 2, significant menthol was detected in dialysate 30min post menthol application (0.89ng, p=0.0002). Relative to baseline, cutaneous vasodilation was elevated from minutes 15-45 and ratings of menthol sensation were elevated from minute 5-60 post menthol application (all p<0.05). Menthol induces cutaneous vasodilation in the skin through multiple vasodilator pathways, including NO, EDHF, and sensory nerves. Topical menthol is detectable in the skin within 30min and is cleared by 60min. Skin blood flow and perceptual measures follow a similar time course as menthol appearance/clearance.

Keywords: Cutaneous; Gas chromatography; Menthol; Microdialysis; Microvasculature; TRPM8.

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Figures

Figure 1
Figure 1. Menthol dose response
Menthol elicited increased vasodilation at all concentrations ≥100 mM. Antagonism with any of L-NAME, TEA, or lidocaine prevented vasodilation. The control site exhibited significantly more vasodilation than the TEA site at all menthol doses ≥50mM and more than the L-NAME and lidocaine sites at all menthol doses ≥100mM. * p<0.05 between control and L-NAME, † p<0.05 between control and TEA, ‡ p<0.05 between control and lidocaine.
Figure 2
Figure 2. Perceptual and physiological responses to topical menthol
(A) Self-reported sensation from topical menthol was significant at every time point between minute 5 and minute 60 post menthol application. (B) Topical menthol significantly increased vasodilation by 15 minutes post-application. Vasodilation remained elevated relative to baseline through minute 45 post-application. (C) Menthol collected from dialysate (ng). Significant menthol was detected at 30 minutes post menthol application. Menthol detection was statistically insignificant at every following time point. * p<0.05 compared to baseline.
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