Advertisement

Enhanced Nonpeptidergic Intraepidermal Fiber Density and an Expanded Subset of Chloroquine-Responsive Trigeminal Neurons in a Mouse Model of Dry Skin Itch

Published:January 29, 2015DOI:https://doi.org/10.1016/j.jpain.2015.01.005

      Highlights

      • Dry skin produced persistent itch without pain in a mouse model.
      • Nonpeptidergic fibers hyperinnervated the epidermis in dry skin.
      • The proportion of sensory neurons responsive to chloroquine was increased.
      • Nonpeptidergic and histamine-independent mechanisms are likely important for dry skin itch.

      Abstract

      Chronic pruritic conditions are often associated with dry skin and loss of epidermal barrier integrity. In this study, repeated application of acetone and ether followed by water (AEW) to the cheek skin of mice produced persistent scratching behavior with no increase in pain-related forelimb wiping, indicating the generation of itch without pain. Cheek skin immunohistochemistry showed a 64.5% increase in total epidermal innervation in AEW-treated mice compared to water-treated controls. This increase was independent of scratching, because mice prevented from scratching by Elizabethan collars showed similar hyperinnervation. To determine the effects of dry skin treatment on specific subsets of peripheral fibers, we examined Ret-positive, calcitonin gene–related peptide (CGRP)–positive, and glial cell line–derived neurotrophic factor family receptor α3 (GFRα3)–positive intraepidermal fiber density. AEW treatment increased Ret-positive fibers but not CGRP-positive or GFRα3-positive fibers, suggesting that a specific subset of nonpeptidergic fibers could contribute to dry skin itch. To test whether trigeminal ganglion neurons innervating the cheek exhibited altered excitability after AEW treatment, primary cultures of retrogradely labeled neurons were examined using whole-cell patch clamp electrophysiology. AEW treatment produced no differences in measures of excitability compared to water-treated controls. In contrast, a significantly higher proportion of trigeminal ganglion neurons was responsive to the nonhistaminergic pruritogen chloroquine after AEW treatment. We conclude that nonpeptidergic, Ret-positive fibers and chloroquine-sensitive neurons may contribute to dry skin pruritus.

      Perspective

      This study examines the underlying neurobiological mechanisms of persistent dry skin itch. Our results indicate that nonpeptidergic epidermal hyperinnervation and nonhistaminergic pruritic receptors are potential targets for chronic pruritus.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Akiyama T.
        • Carstens M.I.
        • Carstens E.
        Enhanced responses of lumbar superficial dorsal horn neurons to intradermal PAR-2 agonist but not histamine in a mouse hindpaw dry skin itch model.
        J Neurophysiol. 2011; 105: 2811-2817
        • Akiyama T.
        • Carstens M.I.
        • Carstens E.
        Spontaneous itch in the absence of hyperalgesia in a mouse hindpaw dry skin model.
        Neurosci Lett. 2010; 484: 62-65
        • Barabas M.E.
        • Kossyreva E.A.
        • Stucky C.L.
        TRPA1 is functionally expressed primarily by IB4-binding, non-peptidergic mouse and rat sensory neurons.
        PLoS One. 2012; 7: e47988
        • Bautista D.M.
        • Jordt S.E.
        • Nikai T.
        • Tsuruda P.R.
        • Read A.J.
        • Poblete J.
        • Yamoah E.N.
        • Basbaum A.I.
        • Julius D.
        TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents.
        Cell. 2006; 124: 1269-1282
        • Bhave G.
        • Hu H.J.
        • Glauner K.S.
        • Zhu W.
        • Wang H.
        • Brasier D.J.
        • Oxford G.S.
        • Gereau R.W.
        Protein kinase C phosphorylation sensitizes but does not activate the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1).
        Proc Natl Acad Sci U S A. 2003; 100: 12480-12485
        • Ciobanu C.
        • Reid G.
        • Babes A.
        Acute and chronic effects of neurotrophic factors BDNF and GDNF on responses mediated by thermo-sensitive TRP channels in cultured rat dorsal root ganglion neurons.
        Brain Res. 2009; 1284: 54-67
        • Cummins T.R.
        • Black J.A.
        • Dib-Hajj S.D.
        • Waxman S.G.
        Glial-derived neurotrophic factor upregulates expression of functional SNS and NaN sodium channels and their currents in axotomized dorsal root ganglion neurons.
        J Neurosci. 2000; 20: 8754-8761
        • Davidson S.
        • Giesler G.J.
        The multiple pathways for itch and their interactions with pain.
        Trends Neurosci. 2010; 33: 550-558
        • Dou Y.C.
        • Hagstromer L.
        • Emtestam L.
        • Johansson O.
        Increased nerve growth factor and its receptors in atopic dermatitis: An immunohistochemical study.
        Arch Dermatol Res. 2006; 298: 31-37
        • Elitt C.M.
        • Malin S.A.
        • Koerber H.R.
        • Davis B.M.
        • Albers K.M.
        Overexpression of artemin in the tongue increases expression of TRPV1 and TRPA1 in trigeminal afferents and causes oral sensitivity to capsaicin and mustard oil.
        Brain Res. 2008; 1230: 80-90
        • Elitt C.M.
        • McIlwrath S.L.
        • Lawson J.J.
        • Malin S.A.
        • Molliver D.C.
        • Cornuet P.K.
        • Koerber H.R.
        • Davis B.M.
        • Albers K.M.
        Artemin overexpression in skin enhances expression of TRPV1 and TRPA1 in cutaneous sensory neurons and leads to behavioral sensitivity to heat and cold.
        J Neurosci. 2006; 26: 8578-8587
        • Fasanella K.E.
        • Christianson J.A.
        • Chanthaphavong R.S.
        • Davis B.M.
        Distribution and neurochemical identification of pancreatic afferents in the mouse.
        J Comp Neurol. 2008; 509: 42-52
        • Fischer A.H.
        • Jacobson K.A.
        • Rose J.
        • Zeller R.
        Hematoxylin and eosin staining of tissue and cell sections.
        CSH Protoc. 2008; 2008 (pdb prot4986)
        • Foster E.L.
        • Simpson E.L.
        • Fredrikson L.J.
        • Lee J.J.
        • Lee N.A.
        • Fryer A.D.
        • Jacoby D.B.
        Eosinophils increase neuron branching in human and murine skin and in vitro.
        PLoS One. 2011; 6: e22029
        • Golden J.P.
        • Hoshi M.
        • Nassar M.A.
        • Enomoto H.
        • Wood J.N.
        • Milbrandt J.
        • Gereau R.W.
        • Johnson Jr., E.M.
        • Jain S.
        RET signaling is required for survival and normal function of nonpeptidergic nociceptors.
        J Neurosci. 2010; 30: 3983-3994
        • 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. 2012; 16: 174-182
        • Horiuchi Y.
        • Bae S.
        • Katayama I.
        Nerve growth factor (NGF) and epidermal nerve fibers in atopic dermatitis model NC/Nga mice.
        J Dermatol Sci. 2005; 39: 56-58
        • Hoshi M.
        • Batourina E.
        • Mendelsohn C.
        • Jain S.
        Novel mechanisms of early upper and lower urinary tract patterning regulated by RetY1015 docking tyrosine in mice.
        Development. 2012; 139: 2405-2415
        • Hu H.J.
        • Bhave G.
        • Gereau R.W.
        Prostaglandin and protein kinase A-dependent modulation of vanilloid receptor function by metabotropic glutamate receptor 5: Potential mechanism for thermal hyperalgesia.
        J Neurosci. 2002; 22: 7444-7452
        • Huang D.
        • Li S.
        • Dhaka A.
        • Story G.M.
        • Cao Y.Q.
        Expression of the transient receptor potential channels TRPV1, TRPA1 and TRPM8 in mouse trigeminal primary afferent neurons innervating the dura.
        Mol Pain. 2012; 8: 66
        • Johansson O.
        • Liang Y.
        • Emtestam L.
        Increased nerve growth factor- and tyrosine kinase A-like immunoreactivities in prurigo nodularis skin—An exploration of the cause of neurohyperplasia.
        Arch Dermatol Res. 2002; 293: 614-619
        • Jordt S.E.
        • Bautista D.M.
        • Chuang H.H.
        • McKemy D.D.
        • Zygmunt P.M.
        • Hogestatt E.D.
        • Meng I.D.
        • Julius D.
        Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1.
        Nature. 2004; 427: 260-265
        • Kamo A.
        • Tominaga M.
        • Tengara S.
        • Ogawa H.
        • Takamori K.
        Inhibitory effects of UV-based therapy on dry skin-inducible nerve growth in acetone-treated mice.
        J Dermatol Sci. 2011; 62: 91-97
        • Klein A.
        • Carstens M.I.
        • Carstens E.
        Facial injections of pruritogens or algogens elicit distinct behavior responses in rats and excite overlapping populations of primary sensory and trigeminal subnucleus caudalis neurons.
        J Neurophysiol. 2011; 106: 1078-1088
        • Lauria G.
        • Borgna M.
        • Morbin M.
        • Lombardi R.
        • Mazzoleni G.
        • Sghirlanzoni A.
        • Pareyson D.
        Tubule and neurofilament immunoreactivity in human hairy skin: Markers for intraepidermal nerve fibers.
        Muscle Nerve. 2004; 30: 310-316
        • Liu Q.
        • Sikand P.
        • Ma C.
        • Tang Z.
        • Han L.
        • Li Z.
        • Sun S.
        • LaMotte R.H.
        • Dong X.
        Mechanisms of itch evoked by beta-alanine.
        J Neurosci. 2012; 32: 14532-14537
        • Liu Q.
        • Tang Z.
        • Surdenikova L.
        • Kim S.
        • Patel K.N.
        • Kim A.
        • Ru F.
        • Guan Y.
        • Weng H.J.
        • Geng Y.
        • Undem B.J.
        • Kollarik M.
        • Chen Z.F.
        • Anderson D.J.
        • Dong X.
        Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus.
        Cell. 2009; 139: 1353-1365
        • Liu Q.
        • Weng H.J.
        • Patel K.N.
        • Tang Z.
        • Bai H.
        • Steinhoff M.
        • Dong X.
        The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia.
        Sci Signal. 2011; 4: ra45
        • Lubbert M.
        • Kyereme J.
        • Schobel N.
        • Beltran L.
        • Wetzel C.H.
        • Hatt H.
        Transient receptor potential channels encode volatile chemicals sensed by rat trigeminal ganglion neurons.
        PLoS One. 2013; 8: e77998
        • 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
        • Malsch P.
        • Andratsch M.
        • Vogl C.
        • Link A.S.
        • Alzheimer C.
        • Brierley S.M.
        • Hughes P.A.
        • Kress M.
        Deletion of interleukin-6 signal transducer gp130 in small sensory neurons attenuates mechanonociception and down-regulates TRPA1 expression.
        J Neurosci. 2014; 34: 9845-9856
        • McNamara C.R.
        • Mandel-Brehm J.
        • Bautista D.M.
        • Siemens J.
        • Deranian K.L.
        • Zhao M.
        • Hayward N.J.
        • Chong J.A.
        • Julius D.
        • Moran M.M.
        • Fanger C.M.
        TRPA1 mediates formalin-induced pain.
        Proc Natl Acad Sci U S A. 2007; 104: 13525-13530
        • Miyamoto T.
        • Nojima H.
        • Shinkado T.
        • Nakahashi T.
        • Kuraishi Y.
        Itch-associated response induced by experimental dry skin in mice.
        Jpn J Pharmacol. 2002; 88: 285-292
        • Molliver D.C.
        • Wright D.E.
        • Leitner M.L.
        • Parsadanian A.S.
        • Doster K.
        • Wen D.
        • Yan Q.
        • Snider W.D.
        IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life.
        Neuron. 1997; 19: 849-861
        • Murota H.
        • Izumi M.
        • Abd El-Latif M.I.
        • Nishioka M.
        • Terao M.
        • Tani M.
        • Matsui S.
        • Sano S.
        • Katayama I.
        Artemin causes hypersensitivity to warm sensation, mimicking warmth-provoked pruritus in atopic dermatitis.
        J Allergy Clin Immunol. 2012; 130: 671-682.e4
        • Nakamura M.
        • Toyoda M.
        • Morohashi M.
        Pruritogenic mediators in psoriasis vulgaris: Comparative evaluation of itch-associated cutaneous factors.
        Br J Dermatol. 2003; 149: 718-730
        • Nojima H.
        • Cuellar J.M.
        • Simons C.T.
        • Carstens M.I.
        • Carstens E.
        Spinal c-fos expression associated with spontaneous biting in a mouse model of dry skin pruritus.
        Neurosci Lett. 2004; 361: 79-82
        • Ostlere L.S.
        • Cowen T.
        • Rustin M.H.
        Neuropeptides in the skin of patients with atopic dermatitis.
        Clin Exp Dermatol. 1995; 20: 462-467
        • Patel T.
        • Yosipovitch G.
        Therapy of pruritus.
        Expert Opin Pharmacother. 2010; 11: 1673-1682
        • Paus R.
        • Schmelz M.
        • Biro T.
        • Steinhoff M.
        Frontiers in pruritus research: Scratching the brain for more effective itch therapy.
        J Clin Invest. 2006; 116: 1174-1186
        • Roggenkamp D.
        • Falkner S.
        • Stab F.
        • Petersen M.
        • Schmelz M.
        • Neufang G.
        Atopic keratinocytes induce increased neurite outgrowth in a coculture model of porcine dorsal root ganglia neurons and human skin cells.
        J Invest Dermatol. 2012; 132: 1892-1900
        • Schmidt M.
        • Dubin A.E.
        • Petrus M.J.
        • Earley T.J.
        • Patapoutian A.
        Nociceptive signals induce trafficking of TRPA1 to the plasma membrane.
        Neuron. 2009; 64: 498-509
        • Shimada S.G.
        • LaMotte R.H.
        Behavioral differentiation between itch and pain in mouse.
        Pain. 2008; 139: 681-687
        • Stander S.
        • Weisshaar E.
        • Mettang T.
        • Szepietowski J.C.
        • Carstens E.
        • Ikoma A.
        • Bergasa N.V.
        • Gieler U.
        • Misery L.
        • Wallengren J.
        • Darsow U.
        • Streit M.
        • Metze D.
        • Luger T.A.
        • Greaves M.W.
        • Schmelz M.
        • Yosipovitch G.
        • Bernhard J.D.
        Clinical classification of itch: A position paper of the International Forum for the Study of Itch.
        Acta Derm Venereol. 2007; 87: 291-294
        • 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
        • Than J.Y.
        • Li L.
        • Hasan R.
        • Zhang X.
        Excitation and modulation of TRPA1, TRPV1, and TRPM8 channel-expressing sensory neurons by the pruritogen chloroquine.
        J Biol Chem. 2013; 288: 12818-12827
        • Tobin D.
        • Nabarro G.
        • Baart de la Faille H.
        • van Vloten W.A.
        • van der Putte S.C.
        • Schuurman H.J.
        Increased number of immunoreactive nerve fibers in atopic dermatitis.
        J Allergy Clin Immunol. 1992; 90: 613-622
        • Tominaga M.
        • Ozawa S.
        • Ogawa H.
        • Takamori K.
        A hypothetical mechanism of intraepidermal neurite formation in NC/Nga mice with atopic dermatitis.
        J Dermatol Sci. 2007; 46: 199-210
        • Tominaga M.
        • Ozawa S.
        • Tengara S.
        • Ogawa H.
        • Takamori K.
        Intraepidermal nerve fibers increase in dry skin of acetone-treated mice.
        J Dermatol Sci. 2007; 48: 103-111
        • Valtcheva M.V.
        • Davidson S.
        • Samineni V.K.
        • Golden J.P.
        • Gereau R.W.
        Dry skin-induced changes in intraepidermal fiber density and sensory neuron physiology.
        J Pain. 2014; 15: 59
        • Valtcheva M.V.
        • Davidson S.
        • Zhao C.
        • Leitges M.
        • Gereau 4th, R.W.
        Protein kinase Cdelta mediates histamine-evoked itch and responses in pruriceptors.
        Mol Pain. 2015; 11: 1
        • Wang J.G.
        • Strong J.A.
        • Xie W.
        • Zhang J.M.
        Local inflammation in rat dorsal root ganglion alters excitability and ion currents in small-diameter sensory neurons.
        Anesthesiology. 2007; 107: 322-332
        • Wilson S.R.
        • Gerhold K.A.
        • Bifolck-Fisher A.
        • Liu Q.
        • Patel K.N.
        • Dong X.
        • Bautista D.M.
        TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch.
        Nat Neurosci. 2011; 14: 595-602
        • 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
        • Wu Z.
        • Yang Q.
        • Crook R.J.
        • O'Neil R.G.
        • Walters E.T.
        TRPV1 channels make major contributions to behavioral hypersensitivity and spontaneous activity in nociceptors after spinal cord injury.
        Pain. 2013; 154: 2130-2141
        • Yamaguchi J.
        • Aihara M.
        • Kobayashi Y.
        • Kambara T.
        • Ikezawa Z.
        Quantitative analysis of nerve growth factor (NGF) in the atopic dermatitis and psoriasis horny layer and effect of treatment on NGF in atopic dermatitis.
        J Dermatol Sci. 2009; 53: 48-54
        • Yamamoto-Kasai E.
        • Imura K.
        • Yasui K.
        • Shichijou M.
        • Oshima I.
        • Hirasawa T.
        • Sakata T.
        • Yoshioka T.
        TRPV3 as a therapeutic target for itch.
        J Invest Dermatol. 2012; 132: 2109-2112
        • Yang D.
        • Gereau R.W.
        Peripheral group II metabotropic glutamate receptors (mGluR2/3) regulate prostaglandin E2-mediated sensitization of capsaicin responses and thermal nociception.
        J Neurosci. 2002; 22: 6388-6393
        • Yosipovitch G.
        Dry skin and impairment of barrier function associated with itch—New insights.
        Int J Cosmet Sci. 2004; 26: 1-7
        • 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