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Logo of neuroscibullNeuroscience Bulletin
 
Neurosci Bull. 2012 April; 28(2): 145–154.
Published online 2012 February 29. doi:  10.1007/s12264-012-1207-9
PMCID: PMC3339413
NIHMSID: NIHMS366637

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

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.

Keywords: oxidative stress, antioxidants, itch, pruritus, TRPA1, TRPV1

Contributor Information

Tong Liu, Phone: +1-617-7328852, Fax: +1-617-7302801, gro.srentrap@5uilt.

Ru-Rong Ji, Phone: +1-617-7328852, Fax: +1-617-7302801, ude.dravrah.hwb.suez@ijrr.

References

[1] Ikoma A., Steinhoff M., Stander S., Yosipovitch G., Schmelz M. The neurobiology of itch. Nat Rev Neurosci. 2006;7:535–547. doi: 10.1038/nrn1950. [PubMed] [Cross Ref]
[2] Bieber T. Atopic dermatitis. N Engl J Med. 2008;358:1483–1494. doi: 10.1056/NEJMra074081. [PubMed] [Cross Ref]
[3] Reich A., Szepietowski J.C. Mediators of pruritus in psoriasis. Mediators Inflamm. 2007;2007:64727. doi: 10.1155/2007/64727. [PMC free article] [PubMed] [Cross Ref]
[4] Kremer A.E., Martens J.J., Kulik W., Rueff F., Kuiper E.M., van Buuren H.R., et al. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology. 2010;139:1008–1018. doi: 10.1053/j.gastro.2010.05.009. [PubMed] [Cross Ref]
[5] Cassano N., Tessari G., Vena G.A., 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. doi: 10.2165/11317620-000000000-00000. [PubMed] [Cross Ref]
[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. doi: 10.2337/dc09-0632. [PMC free article] [PubMed] [Cross Ref]
[7] 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. 2009;12:544–546. doi: 10.1038/nn.2292. [PMC free article] [PubMed] [Cross Ref]
[8] Miller G. Biomedicine. Grasping for clues to the biology of itch. Science. 2007;318:188–189. doi: 10.1126/science.318.5848.188. [PubMed] [Cross Ref]
[9] Bell J.K., McQueen D.S., Rees J.L. 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. doi: 10.1038/sj.bjp.0705754. [PMC free article] [PubMed] [Cross Ref]
[10] Shim W.S., Oh U. Histamine-induced itch and its relationship with pain. Mol Pain. 2008;4:29. doi: 10.1186/1744-8069-4-29. [PMC free article] [PubMed] [Cross Ref]
[11] Liu Q., Tang Z., Surdenikova L., Kim S., Patel K.N., Kim A., et al. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell. 2009;139:1353–1365. doi: 10.1016/j.cell.2009.11.034. [PMC free article] [PubMed] [Cross Ref]
[12] Kini S.P., Delong L.K., Veledar E., McKenzie-Brown A.M., Schaufele M., Chen S.C. The impact of pruritus on quality of life: The skin equivalent of pain. Arch Dermatol. 2011;147:1153–1156. doi: 10.1001/archdermatol.2011.178. [PubMed] [Cross Ref]
[13] Ma Q. Labeled lines meet and talk: population coding of somatic sensations. J Clin Invest. 2010;120:3773–3778. doi: 10.1172/JCI43426. [PMC free article] [PubMed] [Cross Ref]
[14] Finkel T., Holbrook N.J. Oxidants, oxidative stress and the biology of ageing. Nature. 2000;408:239–247. doi: 10.1038/35041687. [PubMed] [Cross Ref]
[15] Klein J.A., Ackerman S.L. Oxidative stress, cell cycle, and neurodegeneration. J Clin Invest. 2003;111:785–793. [PMC free article] [PubMed]
[16] Feldman E.L. Oxidative stress and diabetic neuropathy: a new understanding of an old problem. J Clin Invest. 2003;111:431–433. [PMC free article] [PubMed]
[17] Giordano F.J. Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest. 2005;115:500–508. [PMC free article] [PubMed]
[18] Schwartz E.S., Lee I., Chung K., Chung J.M. Oxidative stress in the spinal cord is an important contributor in capsaicin-induced mechanical secondary hyperalgesia in mice. Pain. 2008;138:514–524. doi: 10.1016/j.pain.2008.01.029. [PMC free article] [PubMed] [Cross Ref]
[19] Yowtak J., Lee K.Y., Kim H.Y., Wang J., Kim H.K., Chung K., et al. Reactive oxygen species contribute to neuropathic pain by reducing spinal GABA release. Pain. 2011;152:844–852. doi: 10.1016/j.pain.2010.12.034. [PMC free article] [PubMed] [Cross Ref]
[20] Sun Y.G., Chen Z.F. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature. 2007;448:700–703. doi: 10.1038/nature06029. [PubMed] [Cross Ref]
[21] Sun Y.G., Zhao Z.Q., Meng X.L., Yin J., Liu X.Y., Chen Z.F. Cellular basis of itch sensation. Science. 2009;325:1531–1534. doi: 10.1126/science.1174868. [PMC free article] [PubMed] [Cross Ref]
[22] Liu T., Xu Z.Z., Park C.K., Berta T., Ji R.R. Toll-like receptor 7 mediates pruritus. Nat Neurosci. 2010;13:1460–1462. doi: 10.1038/nn.2683. [PMC free article] [PubMed] [Cross Ref]
[23] Patel K.N., Dong X. An itch to be scratched. Neuron. 2010;68:334–339. doi: 10.1016/j.neuron.2010.10.018. [PMC free article] [PubMed] [Cross Ref]
[24] Bickers D.R., Athar M. Oxidative stress in the pathogenesis of skin disease. J Invest Dermatol. 2006;126:2565–2575. doi: 10.1038/sj.jid.5700340. [PubMed] [Cross Ref]
[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. doi: 10.1016/S0168-8278(01)00171-4. [PubMed] [Cross Ref]
[26] Tarng D.C., Huang T.P., Wei Y.H., Liu T.Y., Chen H.W., Wen C.T., 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. doi: 10.1053/ajkd.2000.19086. [PubMed] [Cross Ref]
[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. doi: 10.1016/0014-2999(94)00780-B. [PubMed] [Cross Ref]
[28] Costa R., Manjavachi M.N., Motta E.M., Marotta D.M., Juliano L., Torres H.A., 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. doi: 10.1111/j.1476-5381.2009.00571.x. [PMC free article] [PubMed] [Cross Ref]
[29] Kim H.J., Kim D.K., Kim H., Koh J.Y., Kim K.M., Noh M.S., 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. doi: 10.1038/bjp.2008.220. [PMC free article] [PubMed] [Cross Ref]
[30] McQueen D.S., Noble M.A., Bond S.M. Endothelin-1 activates ETA receptors to cause reflex scratching in BALB/c mice. Br J Pharmacol. 2007;151:278–284. doi: 10.1038/sj.bjp.0707216. [PMC free article] [PubMed] [Cross Ref]
[31] Kwan K.Y., Allchorne A.J., Vollrath M.A., Christensen A.P., Zhang D.S., Woolf C.J., et al. TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction. Neuron. 2006;50:277–289. doi: 10.1016/j.neuron.2006.03.042. [PubMed] [Cross Ref]
[32] Shimada S.G., LaMotte R.H. Behavioral differentiation between itch and pain in mouse. Pain. 2008;139:681–687. doi: 10.1016/j.pain.2008.08.002. [PMC free article] [PubMed] [Cross Ref]
[33] LaMotte R.H., Shimada S.G., Sikand P. Mouse models of acute, chemical itch and pain in humans. Exp Dermatol. 2011;20:778–782. doi: 10.1111/j.1600-0625.2011.01367.x. [PMC free article] [PubMed] [Cross Ref]
[34] Ramabadran K., Bansinath M., Turndorf H., Puig M.M. Tail immersion test for the evaluation of a nociceptive reaction in mice. Methodological considerations. J Pharmacol Methods. 1989;21:21–31. doi: 10.1016/0160-5402(89)90019-3. [PubMed] [Cross Ref]
[35] McNamara C.R., Mandel-Brehm J., Bautista D.M., Siemens J., Deranian K.L., Zhao M., et al. TRPA1 mediates formalin-induced pain. Proc Natl Acad Sci U S A. 2007;104:13525–13530. doi: 10.1073/pnas.0705924104. [PubMed] [Cross Ref]
[36] Nojima H., Simons C.T., Cuellar J.M., Carstens M.I., Moore J.A., Carstens E. Opioid modulation of scratching and spinal c-fos expression evoked by intradermal serotonin. J Neurosci. 2003;23:10784–10790. [PubMed]
[37] Liu X.Y., Liu Z.C., Sun Y.G., Ross M., Kim S., Tsai F.F., et al. Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell. 2011;147:447–458. doi: 10.1016/j.cell.2011.08.043. [PMC free article] [PubMed] [Cross Ref]
[38] Akiyama T., Merrill A.W., Zanotto K., Carstens M.I., 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. doi: 10.1124/jpet.109.152256. [PubMed] [Cross Ref]
[39] Imamachi N., Park G.H., Lee H., Anderson D.J., Simon M.I., Basbaum A.I., 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. doi: 10.1073/pnas.0905605106. [PubMed] [Cross Ref]
[40] Liu Y., Ma Q. Generation of somatic sensory neuron diversity and implications on sensory coding. Curr Opin Neurobiol. 2011;21:52–60. doi: 10.1016/j.conb.2010.09.003. [PMC free article] [PubMed] [Cross Ref]
[41] Ringkamp M., Schepers R.J., Shimada S.G., Johanek L.M., Hartke T.V., Borzan J., et al. A role for nociceptive, myelinated nerve fibers in itch sensation. J Neurosci. 2011;31:14841–14849. doi: 10.1523/JNEUROSCI.3005-11.2011. [PMC free article] [PubMed] [Cross Ref]
[42] Wilson S.R., Gerhold K.A., Bifolck-Fisher A., Liu Q., Patel K.N., Dong X., et al. TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch. Nat Neurosci. 2011;14:595–602. doi: 10.1038/nn.2789. [PMC free article] [PubMed] [Cross Ref]
[43] Bessac B.F., Sivula M., von Hehn C.A., Escalera J., Cohn L., Jordt S.E. TRPA1 is a major oxidant sensor in murine airway sensory neurons. J Clin Invest. 2008;118:1899–1910. doi: 10.1172/JCI34192. [PubMed] [Cross Ref]
[44] Andersson D.A., 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. doi: 10.1523/JNEUROSCI.5369-07.2008. [PMC free article] [PubMed] [Cross Ref]
[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. doi: 10.1172/JCI28553. [PMC free article] [PubMed] [Cross Ref]
[46] Patel K.N., Dong X. Itch: cells, molecules, and circuits. ACS Chem Neurosci. 2011;2:17–25. doi: 10.1021/cn100085g. [PMC free article] [PubMed] [Cross Ref]
[47] 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. doi: 10.1523/JNEUROSCI.1192-11.2011. [PMC free article] [PubMed] [Cross Ref]
[48] Reddy V.B., Iuga A.O., Shimada S.G., LaMotte R.H., Lerner E.A. Cowhage-evoked itch is mediated by a novel cysteine protease: a ligand of protease-activated receptors. J Neurosci. 2008;28:4331–4335. doi: 10.1523/JNEUROSCI.0716-08.2008. [PMC free article] [PubMed] [Cross Ref]
[49] Liu Q., Weng H.J., Patel K.N., 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. doi: 10.1126/scisignal.2001925. [PMC free article] [PubMed] [Cross Ref]
[50] Davidson S., Zhang X., Yoon C.H., Khasabov S.G., Simone D.A., Giesler G.J., Jr The itch-producing agents histamine and cowhage activate separate populations of primate spinothalamic tract neurons. J Neurosci. 2007;27:10007–10014. doi: 10.1523/JNEUROSCI.2862-07.2007. [PMC free article] [PubMed] [Cross Ref]
[51] Sikand P., Shimada S.G., Green B.G., LaMotte R.H. Similar itch and nociceptive sensations evoked by punctate cutaneous application of capsaicin, histamine and cowhage. Pain. 2009;144:66–75. doi: 10.1016/j.pain.2009.03.001. [PMC free article] [PubMed] [Cross Ref]
[52] Mishra S.K., Tisel S.M., Orestes P., Bhangoo S.K., Hoon M.A. TRPV1-lineage neurons are required for thermal sensation. EMBO J. 2011;30:582–593. doi: 10.1038/emboj.2010.325. [PubMed] [Cross Ref]
[53] Liu Y., Abdel S.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. doi: 10.1016/j.neuron.2010.09.008. [PMC free article] [PubMed] [Cross Ref]
[54] Yosipovitch G., Carstens E., McGlone F. Chronic itch and chronic pain: Analogous mechanisms. Pain. 2007;131:4–7. doi: 10.1016/j.pain.2007.04.017. [PubMed] [Cross Ref]
[55] Basbaum A.I., Bautista D.M., Scherrer G., Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139:267–284. doi: 10.1016/j.cell.2009.09.028. [PMC free article] [PubMed] [Cross Ref]
[56] Ji R.R., Kohno T., Moore K.A., Woolf C.J. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci. 2003;26:696–705. doi: 10.1016/j.tins.2003.09.017. [PubMed] [Cross Ref]
[57] Woolf C.J., Salter M.W. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765–1769. doi: 10.1126/science.288.5472.1765. [PubMed] [Cross Ref]
[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. doi: 10.1111/j.1755-5949.2010.00201.x. [PubMed] [Cross Ref]
[59] Liu D.L., Wang W.T., Xing J.L., Hu S.J. Research progress in transient receptor potential vanilloid 1 of sensory nervous system. Neurosci Bull. 2009;25:221–227. doi: 10.1007/s12264-009-0506-2. [PMC free article] [PubMed] [Cross Ref]
[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. doi: 10.1038/jid.2008.440. [PubMed] [Cross Ref]
[61] Shim W.S., Tak M.H., Lee M.H., Kim M., Kim M., Koo J.Y., et al. TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J Neurosci. 2007;27:2331–2337. doi: 10.1523/JNEUROSCI.4643-06.2007. [PubMed] [Cross Ref]
[62] Biro T., Toth B.I., 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]
[63] Trevisani M., Siemens J., Materazzi S., Bautista D.M., 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. doi: 10.1073/pnas.0705923104. [PubMed] [Cross Ref]
[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. doi: 10.1002/cne.20794. [PubMed] [Cross Ref]
[65] Story G.M., Peier A.M., Reeve A.J., Eid S.R., Mosbacher J., Hricik T.R., et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell. 2003;112:819–829. doi: 10.1016/S0092-8674(03)00158-2. [PubMed] [Cross Ref]
[66] Yuan H., Zhang Z.W., Liang L.W., Shen Q., Wang X.D., Ren S.M., et al. Treatment strategies for Parkinson’s disease. Neurosci Bull. 2010;26:66–76. doi: 10.1007/s12264-010-0302-z. [PMC free article] [PubMed] [Cross Ref]
[67] Yuan H., Zheng J.C., Liu P., Zhang S.F., Xu J.Y., Bai L.M. Pathogenesis of Parkinson’s disease: oxidative stress, environmental impact factors and inflammatory processes. Neurosci Bull. 2007;23:125–130. doi: 10.1007/s12264-007-0018-x. [PMC free article] [PubMed] [Cross Ref]

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