title: Somatosensory and vasomotor manifestations of individual and combined stimulation of TRPM8 and TRPA1 using topical L-menthol and trans-cinnamaldehyde in healthy volunteers.
abstract: BACKGROUND
  Activation of TRPM8 and TRPA1 receptors generates cold and cold pain sensations, respectively, and is presumably important in clinical pain manifestations, such as cold hyperalgesia. This study investigated the interaction between TRPM8 and TRPA1 receptors through stimulation of glabrous human skin (volar forearm) by topical administration of 40% L-menthol and 10% trans-cinnamaldehyde (CA), individually and in combination.
  
  
  METHODS
  Sensory manifestations were assessed in 10 healthy volunteers via a platform of 11 quantitative sensory (thermal and mechanical stimuli) and vasomotor tests (skin temperature, perfusion and axon-reflex-flare) in a double-blinded randomized crossover design.
  
  
  RESULTS
  Cold pain threshold was increased (p < 0.01, cold allodynia) by L-menthol alone and L-menthol + CA in combination but unaffected by CA. Mechanical pain threshold was significantly decreased (mechanical hyperalgesia) by all three substances (p < 0.01), with a significant intergroup difference found between CA alone and the less decreased L-menthol + CA (p < 0.05). Application of CA alone and L-menthol + CA in combination showed an increase in skin temperature and perfusion significantly larger than that induced by L-menthol alone (p < 0.05). An axon-reflex-flare was present after CA administration, but was significantly reduced upon addition of L-menthol (p < 0.01).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Denmark.
authors.forename: R V
authors.initials: RV
authors.lastname: Olsen
authors.forename: H H
authors.initials: HH
authors.lastname: Andersen
authors.forename: H G
authors.initials: HG
authors.lastname: Møller
authors.forename: P W
authors.initials: PW
authors.lastname: Eskelund
authors.forename: L
authors.initials: L
authors.lastname: Arendt-Nielsen
mesh_terms: D000171:Acrolein / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000287:Administration, Topical; D000293:Adolescent; D000328:Adult; D000982:Antipruritics / Q000008:administration & dosage / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008610:Menthol / Q000008:administration & dosage / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000187:drug effects*; D059225:Nociception / Q000187:drug effects*; D017288:Pain Threshold / Q000187:drug effects*; D012879:Skin Physiological Phenomena / Q000187:drug effects*; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels / Q000187:drug effects*; D013697:Thermosensing / Q000187:drug effects*; D050051:Transient Receptor Potential Channels / Q000187:drug effects*; D014666:Vasomotor System / Q000187:drug effects; D055815:Young Adult
chemical_list: D000982:Antipruritics; D015220:Calcium Channels; D004338:Drug Combinations; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D050051:Transient Receptor Potential Channels; D008610:Menthol; D000171:Acrolein; C012843:cinnamaldehyde