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Peripheral mechanisms of itch

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Abstract

Detection of environmental stimuli that provoke an aversive response has been shown to involve many receptors in the periphery. Probably the least-studied of these stimuli are those that induce the perception of itch (pruritus), an often-experienced unpleasant stimulus. This review covers the ligands and their receptors which are known to cause primary sensory neuron activation and initiate itch sensation. Also covered are several itch-inducing substances which may act indirectly by activating other cell types in the periphery which then signal to primary neurons. Finally, progress in identifying candidate neurotransmitters that sensory neurons use to propagate the itch signal is discussed.

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References

  1. Sun YG, Chen ZF. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 2007, 448: 700–703.

    Article  PubMed  CAS  Google Scholar 

  2. Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF. Cellular basis of itch sensation. Science 2009, 325: 1531–1534.

    Article  PubMed  CAS  Google Scholar 

  3. Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjork HE. Specific C-receptors for itch in human skin. J Neurosci 1997, 17: 8003–8008.

    PubMed  CAS  Google Scholar 

  4. Schmelz M, Schmidt R, Weidner C, Hilliges M, Torebjork HE, Handwerker HO. Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J Neurophysiol 2003, 89: 2441–2448.

    Article  PubMed  CAS  Google Scholar 

  5. Johanek LM, Meyer RA, Hartke T, Hobelmann JG, Maine DN, LaMotte RH, et al. Psychophysical and physiological evidence for parallel afferent pathways mediating the sensation of itch. J Neurosci 2007, 27: 7490–7497.

    Article  PubMed  CAS  Google Scholar 

  6. Liu Q, Tang Z, Surdenikova L, Kim S, Patel KN, Kim A, et al. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 2009, 139: 1353–1365.

    Article  PubMed  Google Scholar 

  7. Liu XY, Liu ZC, Sun YG, Ross M, Kim S, Tsai FF, et al. Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell 2011, 147: 447–458.

    Article  PubMed  CAS  Google Scholar 

  8. Dong X, Han S, Zylka MJ, Simon MI, Anderson DJ. A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell 2001, 106: 619–632.

    Article  PubMed  CAS  Google Scholar 

  9. Zylka MJ, Dong X, Southwell AL, Anderson DJ. Atypical expansion in mice of the sensory neuron-specific Mrg G protein-coupled receptor family. Proc Nat Acad Sci U S A 2003, 100: 10043–10048.

    Article  CAS  Google Scholar 

  10. Lembo PM, Grazzini E, Groblewski T, O’Donnell D, Roy MO, Zhang J, et al. Proenkephalin A gene products activate a new family of sensory neuron-specific GPCRs. Nat Neurosci 2002, 5: 201–209.

    Article  PubMed  CAS  Google Scholar 

  11. Zhang L, Taylor N, Xie Y, Ford R, Johnson J, Paulsen JE, et al. Cloning and expression of MRG receptors in macaque, mouse, and human. Brain Res Mol Brain Res 2005, 133: 187–197.

    Article  PubMed  CAS  Google Scholar 

  12. Sikand P, Dong X, LaMotte RH. BAM8-22 peptide produces itch and nociceptive sensations in humans independent of histamine release. J Neurosci 2011, 31: 7563–7567.

    Article  PubMed  CAS  Google Scholar 

  13. Wilson SR, Gerhold KA, Bifolck-Fisher A, Liu Q, Patel KN, Dong X, et al. TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch. Nat Neurosci 2011, 14: 595–602.

    Article  PubMed  CAS  Google Scholar 

  14. Chen H, Ikeda SR. Modulation of ion channels and synaptic transmission by a human sensory neuron-specific G-protein-coupled receptor, SNSR4/MrgX1, heterologously expressed in cultured rat neurons. J Neurosci 2004, 24: 5044–5053.

    Article  PubMed  CAS  Google Scholar 

  15. Guan Y, Liu Q, Tang Z, Raja SN, Anderson DJ, Dong X. Masrelated G-protein-coupled receptors inhibit pathological pain in mice. Proc Natl Acad Sci U S A 2010, 107: 15933–15938.

    Article  PubMed  CAS  Google Scholar 

  16. Liu Q, Weng HJ, Patel KN, Tang Z, Bai H, Steinhoff M, et al. The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia. Sci Signal 2011, 4(181): ra45.

    Article  PubMed  CAS  Google Scholar 

  17. Déry O, Corvera CU, Steinhoff M, Bunnett NW. Proteinaseactivated receptors: novel mechanisms of signaling by serine proteases. Am J Physiol 1998, 274(6 Pt 1): C1429–1452.

    PubMed  Google Scholar 

  18. Soh UJ, Dores MR, Chen B, Trejo J. Signal transduction by protease-activated receptors. Br J Pharmacol 2010, 160(2): 191–203.

    Article  PubMed  CAS  Google Scholar 

  19. Amadesi S, Cottrell GS, Divino L, Chapman K, Grady EF, Bautista F, et al. Protease-activated receptor 2 sensitizes TRPV1 by protein kinase Cepsilon- and A-dependent mechanisms in rats and mice. J Physiol 2006, 575: 555–571.

    Article  PubMed  CAS  Google Scholar 

  20. Dai Y, Moriyama T, Higashi T, Togashi K, Kobayashi K, Yamanaka H, et al. Proteinase-activated receptor 2-mediated potentiation of transient receptor potential vanilloid subfamily 1 activity reveals a mechanism for proteinase-induced inflammatory pain. J Neurosci 2004, 24: 4293–4299.

    Article  PubMed  CAS  Google Scholar 

  21. Amadesi S, Nie J, Vergnolle N, Cottrell GS, Grady EF, Trevisani M, et al. Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia. J Neurosci 2004, 24: 4300–4312.

    Article  PubMed  CAS  Google Scholar 

  22. Vellani V, Kinsey AM, Prandini M, Hechtfischer SC, Reeh P, Magherini PC, et al. Protease activated receptors 1 and 4 sensitize TRPV1 in nociceptive neurones. Mol Pain 2010, 6: 61.

    Article  PubMed  Google Scholar 

  23. Steinhoff M, Vergnolle N, Young SH, Tognetto M, Amadesi S, Ennes HS, et al. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med 2000, 6: 151–158.

    Article  PubMed  CAS  Google Scholar 

  24. Zhu WJ, Yamanaka H, Obata K, Dai Y, Kobayashi K, Kozai T, et al. Expression of mRNA for four subtypes of the proteinase-activated receptor in rat dorsal root ganglia. Brain Res 2005, 1041(2): 205–211.

    Article  PubMed  CAS  Google Scholar 

  25. Thomsen JS, Sonne M, Benfeldt E, Jensen SB, Serup J, Menné T. Experimental itch in sodium lauryl sulphate-inflamed and normal skin in humans: a randomized, double-blind, placebo-controlled study of histamine and other inducers of itch. Br J Dermatol 2002, 146: 792–800.

    Article  PubMed  CAS  Google Scholar 

  26. Steinhoff M, Neisius U, Ikoma A, Fartasch M, Heyer G, Skov PS, et al. Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin. J Neurosci 2003, 23: 6176–6180.

    PubMed  CAS  Google Scholar 

  27. Costa R, Marotta DM, Manjavachi MN, Fernandes ES, Lima-Garcia JF, Paszcuk AF, et al. Evidence for the role of neurogenic inflammation components in trypsin-elicited scratching behaviour in mice. Br J Pharmacol 2008, 154: 1094–1103.

    Article  PubMed  CAS  Google Scholar 

  28. Shimada SG, Shimada KA, Collins JG. Scratching behavior in mice induced by the proteinase-activated receptor-2 agonist, SLIGRLNH2. Eur J Pharmacol 2006, 530: 281–283.

    Article  PubMed  CAS  Google Scholar 

  29. Reddy VB, Iuga AO, Shimada SG, LaMotte RH, Lerner EA. Cowhage-evoked itch is mediated by a novel cysteine protease: a ligand of protease-activated receptors. J Neurosci 2008, 28: 4331–4335.

    Article  PubMed  CAS  Google Scholar 

  30. Reddy VB, Lerner EA. Plant cysteine proteases that evoke itch activate protease-activated receptors. Br J Dermatol 2010, 163: 532–535.

    Article  PubMed  CAS  Google Scholar 

  31. Paus R, Schmelz M, Bíró T, Steinhoff M. Frontiers in pruritus research: scratching the brain for more effective itch therapy. J Clin Invest 2006, 116: 1174–1186.

    Article  PubMed  CAS  Google Scholar 

  32. Simons FE, Simons KJ. Histamine and H1-antihistamines: Celebrating a century of progress. J Allergy Clin Immunol 2011, 128: 1139–1150. e4.

    Article  PubMed  CAS  Google Scholar 

  33. Klein A, Carstens MI, 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.

    Article  PubMed  CAS  Google Scholar 

  34. Rao KN, Brown MA. Mast cells: multifaceted immune cells with diverse roles in health and disease. Ann N Y Acad Sci 2008, 1143: 83–104.

    Article  PubMed  CAS  Google Scholar 

  35. Han SK, Mancino V, Simon MI. Phospholipase Cbeta 3 mediates the scratching response activated by the histamine H1 receptor on C-fiber nociceptive neurons. Neuron 2006, 52: 691–703.

    Article  PubMed  CAS  Google Scholar 

  36. Kajihara Y, Murakami M, Imagawa T, Otsuguro K, Ito S, Ohta T. Histamine potentiates acid-induced responses mediating transient receptor potential V1 in mouse primary sensory neurons. Neuroscience 2010, 166: 292–304.

    Article  PubMed  CAS  Google Scholar 

  37. Strakhova MI, Nikkel AL, Manelli AM, Hsieh GC, Esbenshade TA, Brioni JD, et al. Localization of histamine H4 receptors in the central nervous system of human and rat. Brain Res 2009, 1250: 41–48.

    Article  PubMed  CAS  Google Scholar 

  38. Bell JK, McQueen DS, Rees JL. Involvement of histamine H4 and H1 receptors in scratching induced by histamine receptor agonists in Balb C mice. Br J Pharmacol 2004, 142: 374–380.

    Article  PubMed  CAS  Google Scholar 

  39. Dunford PJ, Williams KN, Desai PJ, Karlsson L, McQueen D, Thurmond RL. Histamine H4 receptor antagonists are superior to traditional antihistamines in the attenuation of experimental pruritus. J Allergy Clin Immunol 2007, 119: 176–183.

    Article  PubMed  CAS  Google Scholar 

  40. Rossbach K, Nassenstein C, Gschwandtner M, Schnell D, Sander K, Seifert R, et al. Histamine H1, H3 and H4 receptors are involved in pruritus. Neuroscience 2011, 190: 89–102.

    Article  PubMed  CAS  Google Scholar 

  41. Shim WS, Tak MH, Lee MH, Kim M, Kim M, Koo JY, et al. TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J Neurosci 2007, 27: 2331–2337.

    Article  PubMed  CAS  Google Scholar 

  42. Imamachi N, Park GH, Lee H, Anderson DJ, Simon MI, Basbaum AI, et al. TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. Proc Natl Acad Sci U S A 2009, 106: 11330–11335.

    Article  PubMed  CAS  Google Scholar 

  43. Rossbach K, Wendorff S, Sander K, Stark H, Gutzmer R, Werfel T, et al. Histamine H4 receptor antagonism reduces hapten-induced scratching behaviour but not inflammation. Exp Dermatol 2009, 18: 57–63.

    Article  PubMed  CAS  Google Scholar 

  44. Twycross R, Greaves MW, Handwerker H, Jones EA, Libretto SE, Szepietowski JC, et al. Itch: scratching more than the surface. QJM 2003, 96: 7–26.

    Article  PubMed  CAS  Google Scholar 

  45. Akiyama T, Carstens MI, Carstens E. Facial injections of pruritogens and algogens excite partly overlapping populations of primary and second-order trigeminal neurons in mice. J Neurophysiol 2010, 104: 2442–2450.

    Article  PubMed  CAS  Google Scholar 

  46. Sommer C. Serotonin in pain and analgesia: actions in the periphery. Mol Neurobiol 2004, 30: 117–125.

    Article  PubMed  CAS  Google Scholar 

  47. Yamaguchi T, Nagasawa T, Satoh M, Kuraishi Y. Itch-associated response induced by intradermal serotonin through 5-HT2 receptors in mice. Neurosci Res 1999, 35: 77–83.

    Article  PubMed  CAS  Google Scholar 

  48. Kim DK, Kim HJ, Kim H, Koh JY, Kim KM, Noh MS, et al. Involvement of serotonin receptors 5-HT1 and 5-HT2 in 12(S)-HPETE-induced scratching in mice. Eur J Pharmacol 2008, 579: 390–394.

    Article  PubMed  CAS  Google Scholar 

  49. Bockaert J, Claeysen S, Bécamel C, Dumuis A, Marin P. Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation. Cell Tissue Res 2006, 326: 553–572.

    Article  PubMed  CAS  Google Scholar 

  50. Davenport AP, Maguire JJ. Endothelin. In: Handbook of Experimental Pharmacology. Berlin, Germany: Springer Verlag, 2006: 295–329.

    Google Scholar 

  51. Ferreira SH, Romitelli M, de Nucci G. Endothelin-1 participation in overt and inflammatory pain. J Cardiovasc Pharmacol 1989, 13 (Suppl 5): S220–222.

    Article  PubMed  CAS  Google Scholar 

  52. Katugampola R, Church MK, Clough GF. The neurogenic vasodilator response to endothelin-1: a study in human skin in vivo. Exp Physiol 2000, 85: 839–846.

    Article  PubMed  CAS  Google Scholar 

  53. Trentin PG, Fernandes MB, D’Orléans-Juste P, Rae GA. Endothelin-1 causes pruritus in mice. Exp Biol Med (Maywood) 2006, 231: 1146–1151.

    CAS  Google Scholar 

  54. McQueen DS, Noble MA, Bond SM. Endothelin-1 activates ETA receptors to cause reflex scratching in BALB/c mice. Br J Pharmacol 2007, 151: 278–284.

    Article  PubMed  CAS  Google Scholar 

  55. Namer B, Hilliges M, Orstavik K, Schmidt R, Weidner C, Torebjörk E, et al. Endothelin 1 activates and sensitizes human C-nociceptors. Pain 2008, 137: 41–49.

    Article  PubMed  CAS  Google Scholar 

  56. Khodorova A, Montmayeur JP, Strichartz G. Endothelin receptors and pain. J Pain 2009, 10: 4–28.

    Article  PubMed  CAS  Google Scholar 

  57. Liang J, Kawamata T, Ji W. Molecular signaling of pruritus induced by endothelin-1 in mice. Exp Biol Med (Maywood) 2010, 235: 1300–1305.

    Article  CAS  Google Scholar 

  58. Masaki T, Ninomiya H, Sakamoto A, Okamoto Y. Structural basis of the function of endothelin receptor. Mol Cell Biochem 1999, 190: 153–156.

    Article  PubMed  CAS  Google Scholar 

  59. Giaid A, Gibson SJ, Ibrahim BN, Legon S, Bloom SR, Yanagisawa M, et al. Endothelin 1, an endothelium-derived peptide, is expressed in neurons of the human spinal cord and dorsal root ganglia. Proc Natl Acad Sci U S A 1989, 86: 7634–7638.

    Article  PubMed  CAS  Google Scholar 

  60. Pomonis JD, Rogers SD, Peters CM, Ghilardi JR, Mantyh PW. Expression and localization of endothelin receptors: implications for the involvement of peripheral glia in nociception. J Neurosci 2001, 21: 999–1006.

    PubMed  CAS  Google Scholar 

  61. Zhou Z, Davar G, Strichartz G. Endothelin-1 (ET-1) selectively enhances the activation gating of slowly inactivating tetrodotoxinresistant sodium currents in rat sensory neurons: a mechanism for the pain-inducing actions of ET-1. J Neurosci 2002, 22: 6325–6330.

    PubMed  CAS  Google Scholar 

  62. Yamamoto H, Kawamata T, Ninomiya T, Omote K, Namiki A. Endothelin-1 enhances capsaicin-evoked intracellular Ca2+ response via activation of endothelin a receptor in a protein kinase Cepsilondependent manner in dorsal root ganglion neurons. Neuroscience 2006, 137: 949–960.

    Article  PubMed  CAS  Google Scholar 

  63. Vellani V, Prandini M, Giacomoni C, Pavesi G, Ravegnani L, Magherini PC. Functional endothelin receptors are selectively expressed in isolectin B4-negative sensory neurons and are upregulated in isolectin B4-positive neurons by neurturin and glia-derived neurotropic factor. Brain Res 2011, 1381: 31–37.

    Article  PubMed  CAS  Google Scholar 

  64. Metz M, Lammel V, Gibbs BF, Maurer M. Inflammatory murine skin responses to UV-B light are partially dependent on endothelin-1 and mast cells. Am J Pathol 2006, 169: 815–822.

    Article  PubMed  CAS  Google Scholar 

  65. Hirobe T. Role of keratinocyte-derived factors involved in regulating the proliferation and differentiation of mammalian epidermal melanocytes. Pigment Cell Res 2005, 18: 2–12.

    Article  PubMed  CAS  Google Scholar 

  66. Brandt EB, Sivaprasad U. Th2 cytokines and atopic dermatitis. J Clin Cell Immunol 2011, 2(3). pii: 110.

    PubMed  Google Scholar 

  67. Wills-Karp M, Finkelman FD. Untangling the complex web of IL- 4- and IL-13-mediated signaling pathways. Sci Signal 2008, 1: pe55.

    Article  PubMed  Google Scholar 

  68. Cornelissen C, Lüscher-Firzlaff J, Baron JM, Lüscher B. Signaling by IL-31 and functional consequences. Eur J Cell Biol 2011. [Epub ahead of print]

  69. Zheng T, Oh MH, Oh SY, Schroeder JT, Glick AB, Zhu Z. Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J Invest Dermatol 2009, 129: 742–751.

    Article  PubMed  CAS  Google Scholar 

  70. Dillon SR, Sprecher C, Hammond A, Bilsborough J, Rosenfeld-Franklin M, Presnell SR, et al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol 2004, 5: 752–760.

    Article  PubMed  CAS  Google Scholar 

  71. Bando T, Morikawa Y, Komori T, Senba E. Complete overlap of interleukin-31 receptor A and oncostatin M receptor beta in the adult dorsal root ganglia with distinct developmental expression patterns. Neuroscience 2006, 142: 1263–1271.

    Article  PubMed  CAS  Google Scholar 

  72. Johanek LM, Meyer RA, Friedman RM, Greenquist KW, Shim B, Borzan J, et al. A role for polymodal C-fiber afferents in nonhistaminergic itch. J Neurosci 2008, 23: 7659–7669.

    Article  Google Scholar 

  73. Ringkamp M, Schepers RJ, Shimada SG, Johanek LM, Hartke TV, Borzan J, et al. A role for nociceptive, myelinated nerve fibers in itch sensation. J Neurosci 2011, 31: 14841–14849.

    Article  PubMed  CAS  Google Scholar 

  74. Ma C, Nie H, Gu Q, Sikand P, Lamotte RH. In vivo responses of cutaneous C-mechanosensitive neurons in mouse to punctate chemical stimuli that elicit itch and nociceptive sensations in humans. J Neurophysiol 2012, 107: 357–363.

    Article  PubMed  CAS  Google Scholar 

  75. Davidson S, Zhang X, Yoon CH, Khasabov SG, Simone DA, Giesler GJ Jr. The itch-producing agents histamine and cowhage activate separate populations of primate spinothalamic tract neurons. J Neurosci 2007, 27: 10007–10014.

    Article  PubMed  CAS  Google Scholar 

  76. Sikand P, Shimada SG, Green BG, LaMotte RH. Similar itch and nociceptive sensations evoked by punctate cutaneous application of capsaicin, histamine and cowhage. Pain 2009, 144: 66–75.

    Article  PubMed  CAS  Google Scholar 

  77. Sikand P, Shimada SG, Green BG, LaMotte RH. Sensory responses to injection and punctate application of capsaicin and histamine to the skin. Pain 2011, 152: 2485–2494.

    Article  PubMed  CAS  Google Scholar 

  78. Zylka MJ, Rice FL, Anderson DJ. Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 2005, 45: 17–25.

    Article  PubMed  CAS  Google Scholar 

  79. Wada E, Way J, Lebacq-Verheyden AM, Battey JF. Neuromedin B and gastrin-releasing peptide mRNAs are differentially distributed in the rat nervous system. J Neurosci 1990, 10: 2917–2930.

    PubMed  CAS  Google Scholar 

  80. Jensen RT, Battey JF, Spindel ER, Benya RV. International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states. Pharmacol Rev 2008, 60: 1–42.

    Article  PubMed  CAS  Google Scholar 

  81. Lagerström MC, Rogoz K, Abrahamsen B, Persson E, Reinius B, Nordenankar K, et al. VGLUT2-dependent sensory neurons in the TRPV1 population regulate pain and itch. Neuron 2010, 68: 529–542.

    Article  PubMed  Google Scholar 

  82. Liu Y, Abdel Samad O, Zhang L, Duan B, Tong Q, Lopes C, et al. VGLUT2-dependent glutamate release from nociceptors is required to sense pain and suppress itch. Neuron 2010, 68: 543–556.

    Article  PubMed  CAS  Google Scholar 

  83. Koga K, Chen T, Li XY, Descalzi G, Ling J, Gu J, et al. Glutamate acts as a neurotransmitter for gastrin releasing peptide-sensitive and insensitive itch-related synaptic transmission in mammalian spinal cord. Mol Pain 2011, 7: 47.

    Article  PubMed  CAS  Google Scholar 

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McNeil, B., Dong, X. Peripheral mechanisms of itch. Neurosci. Bull. 28, 100–110 (2012). https://doi.org/10.1007/s12264-012-1202-1

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