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Randomized Controlled Trial
. 2022 Jan:139:104271.
doi: 10.1016/j.mvr.2021.104271. Epub 2021 Oct 28.

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

Affiliations
Randomized Controlled Trial

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

Gabrielle A Dillon et al. Microvasc Res. 2022 Jan.

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 ± 1 yrs) were treated with direct application (3 ml over 8 × 13 cm) of 5% menthol gel (Biofreeze™) or placebo gel on the L4 dermatome, separated by 48 h. 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 ± 6 min, CVC increased at the treated site with menthol (0.12 ± 0.02 vs. 1.36 ± 0.19 flux/mm Hg, p < 0.01) but not the placebo (0.10 ± 0.01 vs. 0.18 ± 0.04 flux/mm Hg, 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 ± 0.06 flux/mm Hg, p < 0.01), but not placebo (0.11 ± 0.02 vs. 0.15 ± 0.03 flux/mm Hg, 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.

Keywords: Cross-limb effect; Cross-over effect; Menthol analgesics; Skin blood flow.

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Figures

Figure 1.
Figure 1.
Schematic displaying experimental set up including the treated (menthol or placebo) L4 dermatome (solid blue box), the untreated contralateral L4 dermatome (striped blue box), and the control (untreated) L5/S1 dermatome (open circle). The treatments (menthol or placebo), as well as the treated and untreated legs were randomized at the first experimental visit, and kept consistent for the second visit. Figure created by BioRender.
Figure 2.
Figure 2.
Both placebo (open circles; 10min d=0.95, 20min d=0.57, and 30min d=0.86) and 5% menthol (closed circles; 10min d=2.04, 20min d =1.58, and 30min d =1.54) gels elicited a colder sensation on the treated leg (panel A) compared to the untreated, contralateral leg (panel B) at all time points post-application. On the treated leg (panel A), the menthol gel elicited a colder sensation compared to the placebo at all time points (10min d=1.41, 20min d=1.29, and 30min d=1.1). On the contralateral, untreated leg (panel B), there was no difference between gels. Some of the error bars cannot be seen as they are smaller than the represented mean symbol. *P < 0.01 vs. Placebo; †P < 0.01 vs. Contralateral, Untreated L4.
Figure 3.
Figure 3.
Baseline (circles) and 40 minutes post-gel application (squares) cutaneous vascular conductance (CVC). There was no difference pre-to-post treatment in the control site (panel A) for either gels. CVC increased at both the treated L4 dermatome (panel B) and the untreated, conralateral L4 dermatome with 5% menthol treatment (panel C). *p<0.01 baseline vs. plateau.

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