Why we scratch an itch: the molecules, cells and circuits of itch

Subjects

Abstract

Itch is described as an irritating sensation that triggers a desire to scratch. However, this definition hardly seems fitting for the millions of people who suffer from intractable itch. Indeed, the Buddhist philosopher Nā´áäāgārjuna more aptly stated, “There is pleasure when an itch is scratched. But to be without an itch is more pleasurable still.” Chronic itch is widespread and very difficult to treat. In this review we focus on the molecules, cells and circuits in the peripheral and central nervous systems that drive acute and chronic itch transmission. Understanding the itch circuitry is critical to developing new therapies for this intractable disease.

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Figure 1: Schematic depicting the cell types involved in the detection of diverse itch stimuli.
Figure 2: Models of peripheral and spinal itch circuitry.

References

  1. 1

    Ikoma, A., Steinhoff, M., Stander, S., Yosipovitch, G. & Schmelz, M. The neurobiology of itch. Nat. Rev. Neurosci. 7, 535–547 (2006).

    CAS  Article  Google Scholar 

  2. 2

    Patel, T. & Yosipovitch, G. Therapy of pruritus. Expert Opin. Pharmacother. 11, 1673–1682 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Elmariah, S.B. & Lerner, E.A. Topical therapies for pruritus. Semin. Cutan. Med. Surg. 30, 118–126 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Davidson, S. & Giesler, G.J. The multiple pathways for itch and their interactions with pain. Trends Neurosci. 33, 550–558 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Ross, S.E. Pain and itch: insights into the neural circuits of aversive somatosensation in health and disease. Curr. Opin. Neurobiol. 21, 880–887 (2011).

    CAS  PubMed  Google Scholar 

  6. 6

    McNeil, B. & Dong, X. Peripheral mechanisms of itch. Neurosci. Bull. 28, 100–110 (2012).

    PubMed  PubMed Central  Google Scholar 

  7. 7

    Akiyama, T. & Carstens, E. Neural processing of itch. Neuroscience 250, 697–714 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Garibyan, L., Rheingold, C.G. & Lerner, E.A. Understanding the pathophysiology of itch. Dermatol. Ther. 26, 84–91 (2013).

    PubMed  Google Scholar 

  9. 9

    Shim, W.S. et al. TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J. Neurosci. 27, 2331–2337 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Imamachi, N. et al. TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. Proc. Natl. Acad. Sci. USA 106, 11330–11335 (2009).

    CAS  Google Scholar 

  11. 11

    Akiyama, T., Carstens, M.I. & Carstens, E. Enhanced scratching evoked by PAR-2 agonist and 5-HT but not histamine in a mouse model of chronic dry skin itch. Pain 151, 378–383 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Wilson, S.R. et al. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell 155, 285–295 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Kim, S.J. et al. Analysis of cellular and behavioral responses to imiquimod reveals a unique itch pathway in transient receptor potential vanilloid 1 (TRPV1)-expressing neurons. Proc. Natl. Acad. Sci. USA 108, 3371–3376 (2011).

    CAS  PubMed  Google Scholar 

  14. 14

    Wilson, S.R. et al. TRPA1 is required for histamine-independent, Mas-related G protein–coupled receptor-mediated itch. Nat. Neurosci. 14, 595–602 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Liu, Q. et al. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 139, 1353–1365 (2009).

    PubMed  PubMed Central  Google Scholar 

  16. 16

    Liu, Q. et al. Mechanisms of itch evoked by β-alanine. J. Neurosci. 32, 14532–14537 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Zylka, M.J., Rice, F.L. & Anderson, D.J. Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45, 17–25 (2005).

    CAS  Article  Google Scholar 

  18. 18

    Cavanaugh, D.J. et al. Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. Proc. Natl. Acad. Sci. USA 106, 9075–9080 (2009).

    CAS  Google Scholar 

  19. 19

    Rau, K.K. et al. Mrgprd enhances excitability in specific populations of cutaneous murine polymodal nociceptors. J. Neurosci. 29, 8612–8619 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Shields, S.D., Cavanaugh, D.J., Lee, H., Anderson, D.J. & Basbaum, A.I. Pain behavior in the formalin test persists after ablation of the great majority of C-fiber nociceptors. Pain 151, 422–429 (2010).

    PubMed  PubMed Central  Google Scholar 

  21. 21

    Mishra, S.K., Tisel, S.M., Orestes, P., Bhangoo, S.K. & Hoon, M.A. TRPV1-lineage neurons are required for thermal sensation. EMBO J. 30, 582–593 (2011).

    CAS  PubMed  Google Scholar 

  22. 22

    Steinhoff, M. et al. Proteinase-activated receptor-2 in human skin: tissue distribution and activation of keratinocytes by mast cell tryptase. Exp. Dermatol. 8, 282–294 (1999).

    CAS  PubMed  Google Scholar 

  23. 23

    Steinhoff, M. et al. Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin. J. Neurosci. 23, 6176–6180 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Shimada, S.G., Shimada, K.A. & Collins, J.G. Scratching behavior in mice induced by the proteinase-activated receptor-2 agonist, SLIGRL-NH2. Eur. J. Pharmacol. 530, 281–283 (2006).

    CAS  PubMed  Google Scholar 

  25. 25

    Liu, Q. et al. The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia. Sci. Signal. 4, ra45 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Reddy, V.B., Shimada, S.G., Sikand, P., Lamotte, R.H. & Lerner, E.A. Cathepsin S elicits itch and signals via protease-activated receptors. J. Invest. Dermatol. 130, 1468–1470 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Kim, N. et al. Overexpression of cathepsin S induces chronic atopic dermatitis in mice. J. Invest. Dermatol. 132, 1169–1176 (2012).

    CAS  PubMed  Google Scholar 

  28. 28

    Liu, T., Xu, Z.Z., Park, C.K., Berta, T. & Ji, R.R. Toll-like receptor 7 mediates pruritus. Nat. Neurosci. 13, 1460–1462 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Liu, T. et al. TLR3 deficiency impairs spinal cord synaptic transmission, central sensitization, and pruritus in mice. J. Clin. Invest. 122, 2195–2207 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Liu, T., Gao, Y.J. & Ji, R.R. Emerging role of Toll-like receptors in the control of pain and itch. Neurosci. Bull. 28, 131–144 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Barton, G.M. & Kagan, J.C. A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nat. Rev. Immunol. 9, 535–542 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Abreu, M.T., Fukata, M. & Arditi, M. TLR signaling in the gut in health and disease. J. Immunol. 174, 4453–4460 (2005).

    CAS  PubMed  Google Scholar 

  33. 33

    Sabroe, I., Parker, L.C., Wilson, A.G., Whyte, M.K. & Dower, S.K. Toll-like receptors: their role in allergy and nonallergic inflammatory disease. Clin. Exp. Allergy 32, 984–989 (2002).

    CAS  PubMed  Google Scholar 

  34. 34

    Wilson, S.R. et al. The ion channel TRPA1 is required for chronic itch. J. Neurosci. 33, 9283–9294 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Chiu, I.M. et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature 501, 52–57 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Salpietro, C. et al. TLR2 and TLR4 gene polymorphisms and atopic dermatitis in Italian children: a multicenter study. Int. J. Immunopathol. Pharmacol. 24, 33–40 (2011).

    CAS  PubMed  Google Scholar 

  37. 37

    Mrabet-Dahbi, S. et al. The Toll-like receptor 2 R753Q mutation modifies cytokine production and Toll-like receptor expression in atopic dermatitis. J. Allergy Clin. Immunol. 121, 1013–1019 (2008).

    CAS  PubMed  Google Scholar 

  38. 38

    Han, L. et al. A subpopulation of nociceptors specifically linked to itch. Nat. Neurosci. 16, 174–182 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    McCoy, E.S. et al. Peptidergic CGRPα primary sensory neurons encode heat and itch and tonically suppress sensitivity to cold. Neuron 78, 138–151 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Roberson, D.P. et al. Activity-dependent silencing reveals functionally distinct itch-generating sensory neurons. Nat. Neurosci. 16, 910–918 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Namer, B. et al. Separate peripheral pathways for pruritus in man. J. Neurophysiol. 100, 2062–2069 (2008).

    PubMed  PubMed Central  Google Scholar 

  42. 42

    Johanek, L.M. et al. A role for polymodal C-fiber afferents in nonhistaminergic itch. J. Neurosci. 28, 7659–7669 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Davidson, S. et al. Pruriceptive spinothalamic tract neurons: physiological properties and projection targets in the primate. J. Neurophysiol. 108, 1711–1723 (2012).

    PubMed  PubMed Central  Google Scholar 

  44. 44

    Lagerström, M.C. et al. VGLUT2-dependent sensory neurons in the TRPV1 population regulate pain and itch. Neuron 68, 529–542 (2010).

    PubMed  PubMed Central  Google Scholar 

  45. 45

    Liu, Y. et al. VGLUT2-dependent glutamate release from nociceptors is required to sense pain and suppress itch. Neuron 68, 543–556 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Sun, Y.G. & Chen, Z.F. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 448, 700–703 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Sun, Y.G. et al. Cellular basis of itch sensation. Science 325, 1531–1534 (2009).

    CAS  Google Scholar 

  48. 48

    Mishra, S.K. & Hoon, M.A. The cells and circuitry for itch responses in mice. Science 340, 968–971 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Mishra, S.K., Holzman, S. & Hoon, M.A. A nociceptive signaling role for neuromedin B. J. Neurosci. 32, 8686–8695 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Sukhtankar, D.D. & Ko, M.C. Physiological function of gastrin-releasing peptide and neuromedin B receptors in regulating itch scratching behavior in the spinal cord of mice. PLoS ONE 8, e67422 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Fleming, M.S. et al. The majority of dorsal spinal cord gastrin releasing peptide is synthesized locally whereas neuromedin B is highly expressed in pain- and itch-sensing somatosensory neurons. Mol. Pain 8, 52 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Zhao, Z.Q. et al. Chronic itch development in sensory neurons requires BRAF signaling pathways. J. Clin. Invest. 123, 4769–4780 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Wang, X. et al. Excitatory superficial dorsal horn interneurons are functionally heterogeneous and required for the full behavioral expression of pain and itch. Neuron 78, 312–324 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Li, M.Z. et al. Molecular mapping of developing dorsal horn-enriched genes by microarray and dorsal/ventral subtractive screening. Dev. Biol. 292, 555–564 (2006).

    CAS  PubMed  Google Scholar 

  55. 55

    Forssmann, W.G. et al. The heart is the center of a new endocrine, paracrine, and neuroendocrine system. Arch. Histol. Cytol. 52 (suppl.), 293–315 (1989).

    PubMed  Google Scholar 

  56. 56

    Zhang, F.X. et al. Inhibition of inflammatory pain by activating B-type natriuretic peptide signal pathway in nociceptive sensory neurons. J. Neurosci. 30, 10927–10938 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Liu, X.Y. et al. Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell 147, 447–458 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Moser, H.R. & Giesler, G.J. Jr. Itch and analgesia resulting from intrathecal application of morphine: contrasting effects on different populations of trigeminothalamic tract neurons. J. Neurosci. 33, 6093–6101 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Xu, Y. et al. Ontogeny of excitatory spinal neurons processing distinct somatic sensory modalities. J. Neurosci. 33, 14738–14748 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Akiyama, T., Iodi Carstens, M. & Carstens, E. Transmitters and pathways mediating inhibition of spinal itch-signaling neurons by scratching and other counterstimuli. PLoS ONE 6, e22665 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Inan, S. & Cowan, A. Nalfurafine, a kappa opioid receptor agonist, inhibits scratching behavior secondary to cholestasis induced by chronic ethynylestradiol injections in rats. Pharmacol. Biochem. Behav. 85, 39–43 (2006).

    CAS  PubMed  Google Scholar 

  62. 62

    Davidson, S., Zhang, X., Khasabov, S.G., Simone, D.A. & Giesler, G.J. Jr. Relief of itch by scratching: state-dependent inhibition of primate spinothalamic tract neurons. Nat. Neurosci. 12, 544–546 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Papoiu, A.D., Coghill, R.C., Kraft, R.A., Wang, H. & Yosipovitch, G. A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch. Neuroimage 59, 3611–3623 (2012).

    PubMed  PubMed Central  Google Scholar 

  64. 64

    Liu, B. et al. TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis. FASEB J. 27, 3549–3563 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Maurer, M. et al. Omalizumab for the treatment of chronic idiopathic or spontaneous urticaria. N. Engl. J. Med. 368, 924–935 (2013).

    CAS  PubMed  Google Scholar 

  66. 66

    Grimstad, O. et al. Anti-interleukin-31-antibodies ameliorate scratching behaviour in NC/Nga mice: a model of atopic dermatitis. Exp. Dermatol. 18, 35–43 (2009).

    CAS  PubMed  Google Scholar 

  67. 67

    Basbaum, A.I., Bautista, D.M., Scherrer, G. & Julius, D. Cellular and molecular mechanisms of pain. Cell 139, 267–284 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Tani, E. & Ishikawa, T. Histamine acts directly on calcitonin gene-related peptide- and substance P-containing trigeminal ganglion neurons as assessed by calcium influx and immunocytochemistry. Auris Nasus Larynx 17, 267–274 (1990).

    CAS  PubMed  Google Scholar 

  69. 69

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

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Gomes, L.O., Hara, D.B. & Rae, G.A. Endothelin-1 induces itch and pain in the mouse cheek model. Life Sci. 91, 628–633 (2012).

    CAS  PubMed  Google Scholar 

  71. 71

    Liang, J., Ji, Q. & Ji, W. Role of transient receptor potential ankyrin subfamily member 1 in pruritus induced by endothelin-1. Neurosci. Lett. 492, 175–178 (2011).

    CAS  PubMed  Google Scholar 

  72. 72

    Kim, D.K. et al. Involvement of serotonin receptors 5-HT1 and 5-HT2 in 12(S)-HPETE-induced scratching in mice. Eur. J. Pharmacol. 579, 390–394 (2008).

    CAS  PubMed  Google Scholar 

  73. 73

    Stefansson, K. et al. Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. J. Invest. Dermatol. 128, 18–25 (2008).

    CAS  PubMed  Google Scholar 

  74. 74

    Tsujii, K., Andoh, T., Lee, J.B. & Kuraishi, Y. Activation of proteinase-activated receptors induces itch-associated response through histamine-dependent and -independent pathways in mice. J. Pharmacol. Sci. 108, 385–388 (2008).

    CAS  PubMed  Google Scholar 

  75. 75

    Zhu, Y. et al. Participation of proteinase-activated receptor-2 in passive cutaneous anaphylaxis-induced scratching behavior and the inhibitory effect of tacrolimus. Biol. Pharm. Bull. 32, 1173–1176 (2009).

    CAS  PubMed  Google Scholar 

  76. 76

    Bautista, D.M., Pellegrino, M. & Tsunozaki, M. TRPA1: a gatekeeper for inflammation. Annu. Rev. Physiol. 75, 181–200 (2013).

    CAS  PubMed  Google Scholar 

  77. 77

    Tominaga, M. & Caterina, M.J. Thermosensation and pain. J. Neurobiol. 61, 3–12 (2004).

    PubMed  Google Scholar 

  78. 78

    Miyamoto, T., Nojima, H., Shinkado, T., Nakahashi, T. & Kuraishi, Y. Itch-associated response induced by experimental dry skin in mice. Jpn. J. Pharmacol. 88, 285–292 (2002).

    CAS  Google Scholar 

  79. 79

    Akiyama, T., Carstens, M.I. & Carstens, E. Spontaneous itch in the absence of hyperalgesia in a mouse hindpaw dry skin model. Neurosci. Lett. 484, 62–65 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Jin, H., He, R., Oyoshi, M. & Geha, R.S. Animal models of atopic dermatitis. J. Invest. Dermatol. 129, 31–40 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Seike, M., Ikeda, M., Kodama, H., Terui, T. & Ohtsu, H. Inhibition of scratching behaviour caused by contact dermatitis in histidine decarboxylase gene knockout mice. Exp. Dermatol. 14, 169–175 (2005).

    CAS  PubMed  Google Scholar 

  82. 82

    Dey, D.D., Landrum, O. & Oaklander, A.L. Central neuropathic itch from spinal-cord cavernous hemangioma: a human case, a possible animal model, and hypotheses about pathogenesis. Pain 113, 233–237 (2005).

    PubMed  Google Scholar 

  83. 83

    D'Almeida, J.A. et al. Behavioral changes of Wistar rats with experimentally-induced painful diabetic neuropathy. Arq. Neuropsiquiatr. 57, 746–752 (1999).

    CAS  PubMed  Google Scholar 

  84. 84

    Stebbins, K.J. et al. Therapeutic efficacy of AM156, a novel prostanoid DP2 receptor antagonist, in murine models of allergic rhinitis and house dust mite-induced pulmonary inflammation. Eur. J. Pharmacol. 638, 142–149 (2010).

    CAS  PubMed  Google Scholar 

  85. 85

    Zheng, T. et al. Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J. Invest. Dermatol. 129, 742–751 (2009).

    CAS  PubMed  Google Scholar 

  86. 86

    Hansson, L. et al. Epidermal overexpression of stratum corneum chymotryptic enzyme in mice: a model for chronic itchy dermatitis. J. Invest. Dermatol. 118, 444–449 (2002).

    CAS  PubMed  Google Scholar 

  87. 87

    Konishi, H. et al. IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions. Proc. Natl. Acad. Sci. USA 99, 11340–11345 (2002).

    CAS  PubMed  Google Scholar 

  88. 88

    Briot, A. et al. Par2 inactivation inhibits early production of TSLP, but not cutaneous inflammation, in Netherton syndrome adult mouse model. J. Invest. Dermatol. 130, 2736–2742 (2010).

    CAS  PubMed  Google Scholar 

  89. 89

    Brandt, E.B., Gibson, A.M., Bass, S., Rydyznski, C. & Khurana Hershey, G.K. Exacerbation of allergen-induced eczema in TLR4- and TRIF-deficient mice. J. Immunol. 191, 3519–3525 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Turner, M.J. et al. Topical application of a vitamin D analogue exacerbates atopic dermatitis and induces the atopic dermatitis-like phenotype in Stat6VT mice. Pediatr. Dermatol. 30, 574–578 (2013).

    PubMed  PubMed Central  Google Scholar 

  91. 91

    Nakajima, K. et al. Barrier abnormality due to ceramide deficiency leads to psoriasiform inflammation in a mouse model. J. Invest. Dermatol. 133, 2555–2565 (2013).

    CAS  PubMed  Google Scholar 

  92. 92

    Yockey, L.J. et al. The absence of a microbiota enhances TSLP expression in mice with defective skin barrier but does not affect the severity of their allergic inflammation. J. Invest. Dermatol. 133, 2714–2721 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Yoo, J. et al. Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J. Exp. Med. 202, 541–549 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Oh, M.H. et al. TRPA1-dependent pruritus in IL-13-induced chronic atopic dermatitis. J. Immunol. 191, 5371–5382 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Wallace, K. et al. The PXR is a drug target for chronic inflammatory liver disease. J. Steroid Biochem. Mol. Biol. 120, 137–148 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Belghiti, M. et al. Potentiation of the transient receptor potential vanilloid 1 channel contributes to pruritogenesis in a rat model of liver disease. J. Biol. Chem. 288, 9675–9685 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Yilinuer, H., Yamaoka, J. & Kawana, S. Effect of epinastine hydrochloride on murine self-scratching behavior after skin-scratching stimulation. Arch. Dermatol. Res. 302, 19–26 (2010).

    CAS  PubMed  Google Scholar 

  98. 98

    Honma, Y. et al. Cyclooxygenase-1 inhibition delays recovery of the cutaneous barrier disruption caused by mechanical scratching in mice. Br. J. Dermatol. 156, 1178–1187 (2007).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to M. Pellegrino for critical comments on the manuscript. This work was supported by US National Institutes of Health (NIH) grants AR059385 and DOD007123A (D.M.B.), the intramural research program of the NIH NIDCR (M.A.H.) and a US National Science Foundation Fellowship (S.R.W.).

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Correspondence to Diana M Bautista.

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All authors are in the process of filing a patent application related to some of the results described in this manuscript.

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Bautista, D., Wilson, S. & Hoon, M. Why we scratch an itch: the molecules, cells and circuits of itch. Nat Neurosci 17, 175–182 (2014). https://doi.org/10.1038/nn.3619

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