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

  • Hjalte H. Andersen
    Affiliations
    Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
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  • Parisa Gazerani
    Affiliations
    Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
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  • Lars Arendt-Nielsen
    Correspondence
    Address reprint requests to Lars Arendt-Nielsen, PhD, Dr. Med, Fredrik Bajers Vej 7, Bld D3, Aalborg E DK-9220, Denmark.
    Affiliations
    Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg, Denmark
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      Highlights

      • Topical 10% trans-cinnamaldehyde evoked pain, neurogenic inflammation, and hyperalgesia.
      • Co-administration of 40% L-menthol alleviated several of these established sensory symptoms.
      • L-menthol's counterirritant effect likely occurs through spinal inhibition and through peripheral antagonism.
      • Transient receptor potential cation channel M8 agonists could be useful as topical anti-hyperalgesics.

      Abstract

      The transient receptor potential cation channel subfamily M 8 (TRPM8) agonist L-menthol has been used traditionally for its topical counterirritant properties. Although the use of topical L-menthol for pain is casuistically established, evidence regarding its efficacy is negligible. This study aimed to characterize the effect of L-menthol as a counterirritant on cutaneous pain and hyperalgesia provoked by topical application of the transient receptor potential cation channel, subfamily A, member 1 (TRPA1) agonist trans-cinnamaldehyde (CA). In a randomized, double-blinded study CA was applied to a 3 × 3-cm area of the volar forearm evoking neurogenic inflammation, pain, mechanical, and thermal hyperalgesia in 14 healthy volunteers. In different sessions, 10% CA alone or 40% L-menthol applied simultaneously with 10% CA were administered for 20 minutes, throughout which the subjects rated the pain intensity on a visual analogue scale of 0 to 10. Extensive quantitative sensory testing was conducted and superficial blood flow (neurogenic inflammation) was recorded. Administration of CA evoked spontaneous pain, neurogenic inflammation, thermal hyperalgesia, and primary and secondary mechanical hyperalgesia. Coadministration of topical L-menthol reduced spontaneous pain intensity (P < .01), neurogenic inflammation (P < .01), primary mechanical hyperalgesia (P < .05), secondary mechanical hyperalgesia (P < .05), and heat hyperalgesia (P < .05), but not cold hyperalgesia. L-menthol exhibited inhibitory effects on simultaneously established pain, hypersensitivity, and neurogenic inflammation in a human TRPA1-induced pain model. Potent TRPM8 agonists could be useful as topical antihyperalgesics. The study and the trial protocol is registered and approved by the local research ethics committee under the jurisdiction of the Danish Medicines Agency number N-20130005. The protocol also is registered at Clinicaltrials.gov under NCT02653703.

      Perspective

      Drugs interacting with transient receptor potential channels are of great therapeutic potential. In the present study we established cutaneous pain and hyperalgesia using the TRPA1 agonist CA. Subsequently, we showed that the frequently used topical counterirritant and TRPM8 agonist, L-menthol, decreased evoked pain, hyperalgesia, and inflammation, indicating direct and indirect antinociceptive mechanisms.

      Key words

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      References

        • Albin K.C.
        • Carstens M.I.
        • Carstens E.
        Modulation of oral heat and cold pain by irritant chemicals.
        Chem Senses. 2008; 33: 3-15
        • Andersen H.
        • Poulsen J.
        • Uchida Y.
        • Nikbakht A.
        • Arendt-Nielsen L.
        • Gazerani P.
        Cold and L-menthol-induced sensitization in healthy volunteers-a cold hypersensitivity analogue to the heat/capsaicin model.
        Pain. 2015; 156: 880-889
        • Andersen H.H.
        • Olsen R.V.
        • Møller H.G.
        • Eskelund P.W.
        • Gazerani P.
        • Arendt-Nielsen L.
        A review of topical high-concentration L-menthol as a translational model of cold allodynia and hyperalgesia.
        Eur J Pain. 2013; 18: 315-325
        • Averbeck B.
        • Rucker F.
        • Laubender R.P.
        • Carr R.W.
        Thermal grill-evoked sensations of heat correlate with cold pain threshold and are enhanced by menthol and cinnamaldehyde.
        Eur J Pain. 2013; 17: 724-734
        • Baumgärtner U.
        • Greffrath W.
        • Treede R.D.
        Contact heat and cold, mechanical, electrical and chemical stimuli to elicit small fiber-evoked potentials: Merits and limitations for basic science and clinical use.
        Neurophysiol Clin. 2012; 42: 267-280
        • Bautista D.M.
        • Siemens J.
        • Glazer J.M.
        • Tsuruda P.R.
        • Basbaum A.I.
        • Stucky C.L.
        • Jordt S.E.
        • Julius D.
        The menthol receptor TRPM8 is the principal detector of environmental cold.
        Nature. 2007; 448: 204-208
        • Bautista D.M.
        • Wilson S.R.
        • Hoon M.A.
        Why we scratch an itch: the molecules, cells and circuits of itch.
        Nat Neurosci. 2014; 17: 175-182
        • Binder A.
        • Stengel M.
        • Klebe O.
        • Wasner G.
        • Baron R.
        Topical high-concentration (40%) menthol-somatosensory profile of a human surrogate pain model.
        J Pain. 2011; 12: 764-773
        • Boudreau S.A.
        • Badsberg S.
        • Christensen S.W.
        • Egsgaard L.L.
        Digital pain drawings.
        Clin J Pain. 2016; 32: 139-145
        • Brenaut E.
        • Garlantezec R.
        • Talour K.
        • Misery L.
        Itch characteristics in five dermatoses: Non-atopic eczema, atopic dermatitis, urticaria, psoriasis and scabies.
        Acta Derm Venereol. 2013; 93: 573-574
        • Bromma B.
        • Scharein E.
        • Darsow U.
        • Ring J.
        Effects of menthol and cold on histamine-induced itch and skin reactions in man.
        Neurosci Lett. 1995; 187: 157-160
        • Campero M.
        • Bostock H.
        Unmyelinated afferents in human skin and their responsiveness to low temperature.
        Neurosci Lett. 2010; 470: 188-192
        • Cervero F.
        • Laird J.M.
        Visceral pain.
        Lancet. 1999; 353: 2145-2148
        • Cevikbas F.
        • Wang X.
        • Akiyama T.
        • Kempkes C.
        • Savinko T.
        • Antal A.
        • Kukova G.
        • Buhl T.
        • Ikoma A.
        • Buddenkotte J.
        • Soumelis V.
        • Feld M.
        • Alenius H.
        • Dillon S.R.
        • Carstens E.
        • Homey B.
        • Basbaum A.
        • Steinhoff M.
        A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1.
        J Allergy Clin Immunol. 2014; 133: 448-460
        • Davies S.J.
        • Harding L.M.
        • Baranowski A.P.
        A novel treatment of postherpetic neuralgia using peppermint oil.
        Clin J Pain. 2002; 18: 200-202
        • Eccles R.
        Menthol and related cooling compounds.
        J Pharm Pharmacol. 1994; 46: 618-630
        • Ernst E.
        • Fialka V.
        Ice freezes pain? A review of the clinical effectiveness of analgesic cold therapy.
        J Pain Symptom Manage. 1994; 9: 56-59
        • FDA
        External analgesic drug products for over-the-counter human use; Reopening of the administrative record and amendment of tentative final monograph.
        Fed Regist. 2003; 68: 42324-42327
        • Galeotti N.
        • Di Cesare Mannelli L.
        • Mazzanti G.
        • Bartolini A.
        • Ghelardini C.
        Menthol: A natural analgesic compound.
        Neurosci Lett. 2002; 322: 145-148
        • Gaudioso C.
        • Hao J.
        • Martin-Eauclaire M.F.
        • Gabriac M.
        • Delmas P.
        Menthol pain relief through cumulative inactivation of voltage-gated sodium channels.
        Pain. 2012; 153: 473-484
        • Green B.G.
        • McAuliffe B.L.
        Menthol desensitization of capsaicin irritation. Evidence of a short-term anti-nociceptive effect.
        Physiol Behav. 2000; 68: 631-639
        • Groetzner P.
        • Weidner C.
        The human vasodilator axon reflex - An exclusively peripheral phenomenon?.
        Pain. 2010; 149: 71-75
        • Han L.
        • Ma C.
        • Liu Q.
        • Weng H.J.
        • Cui Y.
        • Tang Z.
        • Kim Y.
        • Nie H.
        • Qu L.
        • Patel K.N.
        • Li Z.
        • McNeil B.
        • He S.
        • Guan Y.
        • Xiao B.
        • Lamotte R.H.
        • Dong X.
        A subpopulation of nociceptors specifically linked to itch.
        Nat Neurosci. 2013; 16: 174-182
        • Hatem S.
        • Attal N.
        • Willer J.C.
        • Bouhassira D.
        Psychophysical study of the effects of topical application of menthol in healthy volunteers.
        Pain. 2006; 122: 190-196
        • Højland C.R.
        • Andersen H.H.
        • Poulsen J.N.
        • Arendt-Nielsen L.
        • Gazerani P.
        A human surrogate model of itch utilizing the TRPA1 agonist trans-cinnamaldehyde.
        Acta Derm Venereol. 2015; 22: 798-803
        • Jain A.
        • Brönneke S.
        • Kolbe L.
        • Stäb F.
        • Wenck H.
        • Neufang G.
        TRP-channel-specific cutaneous eicosanoid release patterns.
        Pain. 2011; 152: 2765-2772
        • Jänig W.
        Systemic and specific autonomic reactions in pain: Efferent, afferent and endocrine components.
        Eur J Anaesthesiol. 1985; 2: 319-346
        • Karashima Y.
        • Damann N.
        • Prenen J.
        • Talavera K.
        • Segal A.
        • Voets T.
        • Nilius B.
        Bimodal action of menthol on the transient receptor potential channel TRPA1.
        J Neurosci. 2007; 27: 9874-9884
        • Klein A.H.
        • Carstens M.I.
        • Zanotto K.L.
        • Sawyer C.M.
        • Ivanov M.
        • Cheung S.
        • Carstens E.
        Self- and cross-desensitization of oral irritation by menthol and cinnamaldehyde (CA) via peripheral interactions at trigeminal sensory neurons.
        Chem Senses. 2011; 36: 199-208
        • Koltzenburg M.
        • Lundberg L.E.
        • Torebjörk H.E.
        Dynamic and static components of mechanical hyperalgesia in human hairy skin.
        Pain. 1992; 51: 207-219
        • Lischetzki G.
        • Rukwied R.
        • Handwerker H.O.
        • Schmelz M.
        Nociceptor activation and protein extravasation induced by inflammatory mediators in human skin.
        Eur J Pain. 2001; 5: 49-57
        • Liu B.
        • Fan L.
        • Balakrishna S.
        • Sui A.
        • Morris J.B.
        • Jordt S.E.
        TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain.
        Pain. 2013; 154: 2169-2177
        • Löffler H.
        • Kampf G.
        Hand disinfection: How irritant are alcohols?.
        J Hosp Infect. 2008; 70: 44-48
        • Macpherson L.J.
        • Hwang S.W.
        • Miyamoto T.
        • Dubin A.E.
        • Patapoutian A.
        • Story G.M.
        More than cool: Promiscuous relationships of menthol and other sensory compounds.
        Mol Cell Neurosci. 2006; 32: 335-343
        • Mahn F.
        • Hüllemann P.
        • Wasner G.
        • Baron R.
        • Binder A.
        Topical high-concentration menthol: Reproducibility of a human surrogate pain model.
        Eur J Pain. 2014; 18: 1248-1258
        • Malin S.
        • Molliver D.
        • Christianson J.A.
        • Schwartz E.S.
        • Cornuet P.
        • Albers K.M.
        • Davis B.M.
        TRPV1 and TRPA1 function and modulation are target tissue dependent.
        J Neurosci. 2011; 31: 10516-10528
        • Mancini F.
        • Bauleo A.
        • Cole J.
        • Lui F.
        • Porro C.A.
        • Haggard P.
        • Iannetti G.D.
        Whole-body mapping of spatial acuity for pain and touch.
        Ann Neurol. 2014; 75: 917-924
        • Mørch C.D.
        • Gazerani P.
        • Nielsen T.A.
        • Arendt-Nielsen L.
        The UVB cutaneous inflammatory pain model: A reproducibility study in healthy volunteers.
        Int J Physiol Pathophysiol Pharmacol. 2013; 5: 203-215
        • Mukhopadhyay I.
        • Gomes P.
        • Aranake S.
        • Shetty M.
        • Karnik P.
        • Damle M.
        • Kuruganti S.
        • Thorat S.
        • Khairatkar-Joshi N.
        Expression of functional TRPA1 receptor on human lung fibroblast and epithelial cells.
        J Recept Signal Transduct Res. 2011; 31: 350-358
        • Namer B.
        • Kleggetveit I.P.
        • Handwerker H.
        • Schmelz M.
        • Jorum E.
        Role of TRPM8 and TRPA1 for cold allodynia in patients with cold injury.
        Pain. 2008; 139: 63-72
        • Namer B.
        • Seifert F.
        • Handwerker H.
        • Maihöfner C.
        TRPA1 and TRPM8 activation in humans: Effects of cinnamaldehyde and menthol.
        Neuroreport. 2005; 16: 955-959
        • O’Neill J.L.
        • Chan Y.H.
        • Rapp S.R.
        • Yosipovitch G.
        Differences in itch characteristics between psoriasis and atopic dermatitis patients: Results of a Web-based questionnaire.
        Acta Derm Venereol. 2011; 91: 537-540
        • Oh M.H.
        • Oh S.Y.
        • Lu J.
        • Lou H.
        • Myers A.C.
        • Zhu Z.
        • Zheng T.
        TRPA1-dependent pruritus in IL-13-induced chronic atopic dermatitis.
        J Immunol. 2013; 191: 5371-5382
        • Olsen R.V.
        • Andersen H.H.
        • Møller H.G.
        • Eskelund P.W.
        • Arendt-Nielsen L.
        Somatosensory and vasomotor manifestations of individual and combined stimulation of TRPM8 and TRPA1 using topical L-menthol and trans -cinnamaldehyde in healthy volunteers.
        Eur J Pain. 2014; 18: 1333-1342
        • Pan R.
        • Tian Y.
        • Gao R.
        • Li H.
        • Zhao X.
        • Barrett J.E.
        • Hu H.
        Central mechanisms of menthol-induced analgesia.
        J Pharmacol Exp Ther. 2012; 343: 661-672
        • Peier A.M.
        • Moqrich A.
        • Hergarden A.C.
        • Reeve A.J.
        • Andersson D.A.
        • Story G.M.
        • Earley T.J.
        • Dragoni I.
        • McIntyre P.
        • Bevan S.
        • Patapoutian A.
        A TRP channel that senses cold stimuli and menthol.
        Cell. 2002; 108: 705-715
        • Perkins F.
        • Werner M.
        • Persson F.
        • Holte K.
        • Jensen T.S.
        • Kehlet H.
        Development and validation of a brief, descriptive Danish pain questionnaire (BDDPQ).
        Acta Anaesthesiol Scand. 2004; 48: 486-490
        • Petersen K.L.
        • Rowbotham M.C.
        A new human experimental pain model: The heat/capsaicin sensitization model.
        Neuroreport. 1999; 10: 1511-1516
        • Proudfoot C.J.
        • Garry E.M.
        • Cottrell D.F.
        • Rosie R.
        • Anderson H.
        • Robertson D.C.
        • Fleetwood-Walker S.M.
        • Mitchell R.
        Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain.
        Curr Biol. 2006; 16: 1591-1605
        • Roberts K.
        • Shenoy R.
        • Anand P.
        A novel human volunteer pain model using contact heat evoked potentials (CHEP) following topical skin application of transient receptor potential agonists capsaicin, menthol and cinnamaldehyde.
        J Clin Neurosci. 2011; 18: 926-932
        • Rolke R.
        • Magerl W.
        • Campbell K.A.
        • Schalber C.
        • Caspari S.
        • Birklein F.
        • Treede R.D.
        Quantitative sensory testing: A comprehensive protocol for clinical trials.
        Eur J Pain. 2006; 10: 77-88
        • Saarnilehto M.
        • Chapman H.
        • Savinko T.
        • Lindstedt K.
        • Lauerma A.I.
        • Koivisto A.
        Contact sensitizer 2,4-dinitrochlorobenzene is a highly potent human TRPA1 agonist.
        Allergy. 2014; 69: 1424-1427
        • Sandkühler J.
        Models and mechanisms of hyperalgesia and allodynia.
        Physiol Rev. 2009; 89: 707-758
        • Schmelz M.
        • Michael K.
        • Weidner C.
        • Torebjörk H.
        • Handwerker H.
        Which nerve fibers mediate the axon reflex flare in human skin?.
        Neuroreport. 2000; 11: 645-648
        • Sherkheli M.A.
        • Vogt-Eisele A.K.
        • Bura D.
        Beltran Marques LR, Gisselmann G, Hatt H: Characterization of selective TRPM8 ligands and their structure activity response (S.A.R) relationship.
        J Pharm Pharm Sci. 2010; 13: 242-253
        • Sikand P.
        • Dong X.
        • LaMotte R.H.
        BAM8-22 peptide produces itch and nociceptive sensations in humans independent of histamine release.
        J Neurosci. 2011; 31: 7563-7567
        • Silva C.R.
        • Oliveira S.M.
        • Rossato M.F.
        • Dalmolin G.D.
        • Guerra G.P.
        • da Silveira Prudente A.
        • Cabrini D.A.
        • Otuki M.F.
        • Andre E.
        • Ferreira J.
        The involvement of TRPA1 channel activation in the inflammatory response evoked by topical application of cinnamaldehyde to mice.
        Life Sci. 2011; 88: 1077-1087
        • Story G.M.
        • Peier A.M.
        • Reeve A.J.
        • Eid S.R.
        • Mosbacher J.
        • Hricik T.R.
        • Earley T.J.
        • Hergarden A.C.
        • Andersson D.A.
        • Hwang S.W.
        • McIntyre P.
        • Jegla T.
        • Bevan S.
        • Patapoutian A.
        ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures.
        Cell. 2003; 112: 819-829
        • Trevisani M.
        • Smart D.
        • Gunthorpe M.J.
        • Tognetto M.
        • Barbieri M.
        • Campi B.
        • Amadesi S.
        • Gray J.
        • Jerman J.C.
        • Brough S.J.
        • Owen D.
        • Smith G.D.
        • Randall A.D.
        • Harrison S.
        • Bianchi A.
        • Davis J.B.
        • Geppetti P.
        Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1.
        Nat Neurosci. 2002; 5: 546-551
        • VanderEnde D.S.
        • Morrow J.D.
        Release of markedly increased quantities of prostaglandin D2 from the skin in vivo in humans after the application of cinnamic aldehyde.
        J Am Acad Dermatol. 2001; 45: 62-67
        • Viswanath V.
        • Story G.M.
        • Peier A.M.
        • Petrus M.J.
        • Lee V.M.
        • Hwang S.W.
        • Patapoutian A.
        • Jegla T.
        Opposite thermosensor in fruitfly and mouse.
        Nature. 2003; 423: 822-823
        • Wasner G.
        • Naleschinski D.
        • Binder A.
        • Schattschneider J.
        • McLachlan E.M.
        • Baron R.
        The effect of menthol on cold allodynia in patients with neuropathic pain.
        Pain Med. 2008; 9: 354-358
        • Wasner G.
        • Schattschneider J.
        • Binder A.
        • Baron R.
        Topical menthol–A human model for cold pain by activation and sensitization of C nociceptors.
        Brain. 2004; 127: 1159-1171
        • Wilson S.R.
        • Nelson A.M.
        • Batia L.
        • Morita T.
        • Estandian D.
        • Owens D.M.
        • Lumpkin E.A.
        • Bautista D.M.
        The ion channel TRPA1 is required for chronic itch.
        J Neurosci. 2013; 33: 9283-9294
        • Wright A.
        Oil of peppermint as a local anæsthetic.
        Lancet. 1870; 96: 726
        • Xiao B.
        • Patapoutian A.
        Scratching the surface: A role of pain-sensing TRPA1 in itch.
        Nat Neurosci. 2011; 14: 540-542
        • Zanotto K.
        • Carstens M.I.
        • Carstens E.
        Cross-desensitization of responses of rat trigeminal subnucleus caudalis neurons to cinnamaldehyde and menthol.
        Neurosci Lett. 2008; 430: 29-33
        • Zylka M.J.
        • Rice F.L.
        • Anderson D.J.
        Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd.
        Neuron. 2005; 45: 17-25