Somatosensory and vasomotor manifestations of individual and combined stimulation of TRPM8 and TRPA1 using topical L‐menthol and trans‐cinnamaldehyde in healthy volunteers

Abstract

This study elucidates the potential of L-menthol as a counter-irritant to secondary neurogenic inflammation and provides evidence of an intricate interplay between cold receptors TRPA1 and TRPM8, warranting further investigation of the neural coding of cold pain perception.

High-Concentration L-Menthol Exhibits Counter-Irritancy to Neurogenic Inflammation, Thermal and Mechanical Hyperalgesia Caused by Trans-cinnamaldehyde

“…Ethanol was chosen as a vehicle because of 1) its ability to dissolve a high concentration of L-menthol, 2) its low toxicity for an organic solvent, 3) its marginal somatosensory sensory effects and 4) the precedence of using it in literature. 3,4,39,40,43 …”

“…The chosen concentrations were determined by precedence in the literature showing that 10% CA evokes a considerable neurogenic flare and prolonged mechanical hyperalgesia 39,40,43 and that the maximal solubility of pure L-menthol in ethanol is approximately 40%. Ethanol was chosen as a vehicle because of 1) its ability to dissolve a high concentration of L-menthol, 2) its low toxicity for an organic solvent, 3) its marginal somatosensory sensory effects and 4) the precedence of using it in literature.…”

“…Such a procedure has previously been utilized in previous studies using highly odorous compounds to avoid unmasking the investigator and subjects. 24,40,43 The ambient temperature was kept at ≈21 °C in all experimental sessions.…”

“…51 The verbal instructions (in Danish) for participants from the DFNS protocol were derived from the supplementary materials of Olsen et al (2014). 43 The terminology used to describe the induced sensory derangement are defined in Sandkühler (2009). 53 2.5.1.…”

“…57 Topical application of 10% CA has previously been shown to cause mild to moderate pain, mechanical and thermal hyperalgesia and neurogenic inflammation in human skin and rodents. 23,40,43,66 At lower concentrations, topical CA has been found to evoke itch in rodents and also in humans. 25,66 The primary outcome of this study was CA-evoked peak pain intensity monitored for 20 min post application, with versus without L-menthol coapplication, while secondary outcome measures included quantitative sensory testing (QST) parameters and neurogenic inflammation.…”