Skip to main content

Advertisement

Log in

Oxidative stress induces itch via activation of transient receptor potential subtype ankyrin 1 in mice

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

Objective

To investigate the role of oxidative stress in itch-indicative scratching behavior in mice, and furthermore, to define the cellular and molecular mechanisms underlying oxidative stress-mediated itch.

Methods

Scratching behavior was induced by intradermal injection of the oxidants hydrogen peroxide (H2O2) or tert-butylhydroperoxide (tBHP) into the nape of the neck in mice. The mice were observed for 30 min.

Results

Intradermal H2O2 (0.03%–1%) or tBHP (1–30 μmol) elicited robust scratching behavior, displaying an inverted U-shaped dose-response curve. Naloxone, an opioid receptor antagonist, but not morphine, largely suppressed the oxidant-induced scratching. Chlorpheniramine, a histamine H1 receptor antagonist, blocked histamine-but not oxidant-induced scratching, indicating the involvement of a histamine-independent mechanism in oxidant-evoked itch. Further, resiniferatoxin treatment abolished oxidant-induced scratching, suggesting an essential role of C-fibers. Notably, blockade of transient receptor potential subtype ankyrin 1 (TRPA1) with the selective TRPA1 antagonist HC-030031, or genetic deletion of Trpa1 but not Trpv1 (subfamily V, member 1) resulted in a profound reduction in H2O2-evoked scratching. Finally, systemic administration of the antioxidant Nacetyl-L-cysteine or trolox (a water-soluble vitamin E analog) attenuated scratching induced by the oxidants.

Conclusio

Oxidative stress by different oxidants induces profound scratching behavior, which is largely histamine- and TRPV1-independent but TRPA1-dependent. Antioxidants and TRPA1 antagonists may be used to treat human itch conditions associated with oxidative stress.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

    Article  PubMed  CAS  Google Scholar 

  2. Bieber T. Atopic dermatitis. N Engl J Med 2008, 358: 1483–1494.

    Article  PubMed  CAS  Google Scholar 

  3. Reich A, Szepietowski JC. Mediators of pruritus in psoriasis. Mediators Inflamm 2007, 2007: 64727.

    Article  PubMed  Google Scholar 

  4. Kremer AE, Martens JJ, Kulik W, Rueff F, Kuiper EM, van Buuren HR, et al. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology 2010, 139: 1008–1018.

    Article  PubMed  CAS  Google Scholar 

  5. Cassano N, Tessari G, Vena GA, Girolomoni G. Chronic pruritus in the absence of specific skin disease: an update on pathophysiology, diagnosis, and therapy. Am J Clin Dermatol 2010, 11: 399–411.

    Article  PubMed  Google Scholar 

  6. Yamaoka H, Sasaki H, Yamasaki H, Ogawa K, Ohta T, Furuta H, et al. Truncal pruritus of unknown origin may be a symptom of diabetic polyneuropathy. Diabetes Care 2010, 33: 150–155.

    Article  PubMed  Google Scholar 

  7. Davidson S, Zhang X, Khasabov SG, Simone DA, Giesler GJ Jr. Relief of itch by scratching: state-dependent inhibition of primate spinothalamic tract neurons. Nat Neurosci 2009, 12: 544–546.

    Article  PubMed  CAS  Google Scholar 

  8. Miller G. Biomedicine. Grasping for clues to the biology of itch. Science 2007, 318: 188–189.

    Article  PubMed  CAS  Google Scholar 

  9. 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 

  10. Shim WS, Oh U. Histamine-induced itch and its relationship with pain. Mol Pain 2008, 4: 29.

    Article  PubMed  Google Scholar 

  11. 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 

  12. Kini SP, Delong LK, Veledar E, McKenzie-Brown AM, Schaufele M, Chen SC. The impact of pruritus on quality of life: The skin equivalent of pain. Arch Dermatol 2011, 147: 1153–1156.

    Article  PubMed  Google Scholar 

  13. Ma Q. Labeled lines meet and talk: population coding of somatic sensations. J Clin Invest 2010, 120: 3773–3778.

    Article  PubMed  CAS  Google Scholar 

  14. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature 2000, 408: 239–247.

    Article  PubMed  CAS  Google Scholar 

  15. Klein JA, Ackerman SL. Oxidative stress, cell cycle, and neurodegeneration. J Clin Invest 2003, 111: 785–793.

    PubMed  CAS  Google Scholar 

  16. Feldman EL. Oxidative stress and diabetic neuropathy: a new understanding of an old problem. J Clin Invest 2003, 111: 431–433.

    PubMed  CAS  Google Scholar 

  17. Giordano FJ. Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest 2005, 115: 500–508.

    PubMed  CAS  Google Scholar 

  18. Schwartz ES, Lee I, Chung K, Chung JM. Oxidative stress in the spinal cord is an important contributor in capsaicin-induced mechanical secondary hyperalgesia in mice. Pain 2008, 138: 514–524.

    Article  PubMed  CAS  Google Scholar 

  19. Yowtak J, Lee KY, Kim HY, Wang J, Kim HK, Chung K, et al. Reactive oxygen species contribute to neuropathic pain by reducing spinal GABA release. Pain 2011, 152: 844–852.

    Article  PubMed  CAS  Google Scholar 

  20. 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 

  21. 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 

  22. Liu T, Xu ZZ, Park CK, Berta T, Ji RR. Toll-like receptor 7 mediates pruritus. Nat Neurosci 2010, 13: 1460–1462.

    Article  PubMed  CAS  Google Scholar 

  23. Patel KN, Dong X. An itch to be scratched. Neuron 2010, 68: 334–339.

    Article  PubMed  CAS  Google Scholar 

  24. Bickers DR, Athar M. Oxidative stress in the pathogenesis of skin disease. J Invest Dermatol 2006, 126: 2565–2575.

    Article  PubMed  CAS  Google Scholar 

  25. Kitada T, Seki S, Iwai S, Yamada T, Sakaguchi H, Wakasa K. In situ detection of oxidative DNA damage, 8-hydroxydeoxyguanosine, in chronic human liver disease. J Hepatol 2001, 35: 613–618.

    Article  PubMed  CAS  Google Scholar 

  26. Tarng DC, Huang TP, Wei YH, Liu TY, Chen HW, Wen CT, et al. 8-hydroxy-2′-deoxyguanosine of leukocyte DNA as a marker of oxidative stress in chronic hemodialysis patients. Am J Kidney Dis 2000, 36: 934–944.

    Article  PubMed  CAS  Google Scholar 

  27. Kuraishi Y, Nagasawa T, Hayashi K, Satoh M. Scratching behavior induced by pruritogenic but not algesiogenic agents in mice. Eur J Pharmacol 1995, 275: 229–233.

    Article  PubMed  CAS  Google Scholar 

  28. Costa R, Manjavachi MN, Motta EM, Marotta DM, Juliano L, Torres HA, et al. The role of kinin B1 and B2 receptors in the scratching behaviour induced by proteinase-activated receptor-2 agonists in mice. Br J Pharmacol 2010, 159: 888–897.

    Article  PubMed  CAS  Google Scholar 

  29. Kim HJ, Kim DK, Kim H, Koh JY, Kim KM, Noh MS, et al. Involvement of the BLT2 receptor in the itch-associated scratching induced by 12-(S)-lipoxygenase products in ICR mice. Br J Pharmacol 2008, 154: 1073–1078.

    Article  PubMed  CAS  Google Scholar 

  30. 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 

  31. Kwan KY, Allchorne AJ, Vollrath MA, Christensen AP, Zhang DS, Woolf CJ, et al. TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction. Neuron 2006, 50: 277–289.

    Article  PubMed  CAS  Google Scholar 

  32. Shimada SG, LaMotte RH. Behavioral differentiation between itch and pain in mouse. Pain 2008, 139: 681–687.

    Article  PubMed  Google Scholar 

  33. LaMotte RH, Shimada SG, Sikand P. Mouse models of acute, chemical itch and pain in humans. Exp Dermatol 2011, 20: 778–782.

    Article  PubMed  CAS  Google Scholar 

  34. Ramabadran K, Bansinath M, Turndorf H, Puig MM. Tail immersion test for the evaluation of a nociceptive reaction in mice. Methodological considerations. J Pharmacol Methods 1989, 21: 21–31.

    Article  PubMed  CAS  Google Scholar 

  35. McNamara CR, Mandel-Brehm J, Bautista DM, Siemens J, Deranian KL, Zhao M, et al. TRPA1 mediates formalin-induced pain. Proc Natl Acad Sci U S A 2007, 104: 13525–13530.

    Article  PubMed  CAS  Google Scholar 

  36. Nojima H, Simons CT, Cuellar JM, Carstens MI, Moore JA, Carstens E. Opioid modulation of scratching and spinal c-fos expression evoked by intradermal serotonin. J Neurosci 2003, 23: 10784–10790.

    PubMed  CAS  Google Scholar 

  37. 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 

  38. Akiyama T, Merrill AW, Zanotto K, Carstens MI, Carstens E. Scratching behavior and Fos expression in superficial dorsal horn elicited by protease-activated receptor agonists and other itch mediators in mice. J Pharmacol Exp Ther 2009, 329: 945–951.

    Article  PubMed  CAS  Google Scholar 

  39. 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 

  40. Liu Y, Ma Q. Generation of somatic sensory neuron diversity and implications on sensory coding. Curr Opin Neurobiol 2011, 21: 52–60.

    Article  PubMed  Google Scholar 

  41. 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 

  42. 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 

  43. Bessac BF, Sivula M, von Hehn CA, Escalera J, Cohn L, Jordt SE. TRPA1 is a major oxidant sensor in murine airway sensory neurons. J Clin Invest 2008, 118: 1899–1910.

    Article  PubMed  CAS  Google Scholar 

  44. Andersson DA, Gentry C, Moss S, Bevan S. Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. J Neurosci 2008, 28: 2485–2494.

    Article  PubMed  CAS  Google Scholar 

  45. 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.

    Article  PubMed  CAS  Google Scholar 

  46. Patel KN, Dong X. Itch: cells, molecules, and circuits. ACS Chem Neurosci 2011, 2: 17–25.

    Article  PubMed  Google Scholar 

  47. 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 

  48. 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 

  49. 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: ra45.

    Article  PubMed  CAS  Google Scholar 

  50. 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 

  51. 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 

  52. Mishra SK, Tisel SM, Orestes P, Bhangoo SK, Hoon MA. TRPV1-lineage neurons are required for thermal sensation. EMBO J 2011, 30: 582–593.

    Article  PubMed  CAS  Google Scholar 

  53. Liu Y, Abdel SO, 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 

  54. Yosipovitch G, Carstens E, McGlone F. Chronic itch and chronic pain: Analogous mechanisms. Pain 2007, 131: 4–7.

    Article  PubMed  Google Scholar 

  55. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell 2009, 139: 267–284.

    Article  PubMed  CAS  Google Scholar 

  56. Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci 2003, 26: 696–705.

    Article  PubMed  CAS  Google Scholar 

  57. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000, 288: 1765–1769.

    Article  PubMed  CAS  Google Scholar 

  58. Cevikbas F, Steinhoff M, Ikoma A. Role of spinal neurotransmitter receptors in itch: New insights into therapies and drug development. CNS Neurosci Ther 2010, 17: 742–749.

    Article  PubMed  Google Scholar 

  59. Liu DL, Wang WT, Xing JL, Hu SJ. Research progress in transient receptor potential vanilloid 1 of sensory nervous system. Neurosci Bull 2009, 25: 221–227.

    Article  PubMed  CAS  Google Scholar 

  60. Steinhoff M, Biro T. A TR(I)P to pruritus research: role of TRPV3 in inflammation and itch. J Invest Dermatol 2009, 129: 531–535.

    Article  PubMed  CAS  Google Scholar 

  61. 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 

  62. Biro T, Toth BI, Marincsak R, Dobrosi N, Geczy T, Paus R. TRP channels as novel players in the pathogenesis and therapy of itch. Biochim Biophys Acta 2007, 1772: 1004–1021.

    PubMed  CAS  Google Scholar 

  63. Trevisani M, Siemens J, Materazzi S, Bautista DM, Nassini R, Campi B, et al. 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A 2007, 104: 13519–13524.

    Article  PubMed  CAS  Google Scholar 

  64. Kobayashi K, Fukuoka T, Obata K, Yamanaka H, Dai Y, Tokunaga A, et al. Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with a-delta/c-fibers and colocalization with trk receptors. J Comp Neurol 2005, 493: 596–606.

    Article  PubMed  CAS  Google Scholar 

  65. Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 2003, 112: 819–829.

    Article  PubMed  CAS  Google Scholar 

  66. Yuan H, Zhang ZW, Liang LW, Shen Q, Wang XD, Ren SM, et al. Treatment strategies for Parkinson’s disease. Neurosci Bull 2010, 26: 66–76.

    Article  PubMed  CAS  Google Scholar 

  67. Yuan H, Zheng JC, Liu P, Zhang SF, Xu JY, Bai LM. Pathogenesis of Parkinson’s disease: oxidative stress, environmental impact factors and inflammatory processes. Neurosci Bull 2007, 23: 125–130.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Tong Liu or Ru-Rong Ji.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, T., Ji, RR. Oxidative stress induces itch via activation of transient receptor potential subtype ankyrin 1 in mice. Neurosci. Bull. 28, 145–154 (2012). https://doi.org/10.1007/s12264-012-1207-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-012-1207-9

Keywords

Navigation