Pruritus pp 407-414 | Cite as

NK-1 Antagonists

Chapter
First Online:

Abstract

The skin contains a vital mediator of pro-inflammatory mechanisms called substance P (SP). SP targets various cells associated with the cutaneous induction of pruritus, for example, keratinocytes, mast cells and fibroblasts. Due to this unique characteristic, it is a potentially valuable subject for novel therapies. A substantial antipruritic effect of SP antagonists on both chronic and acute pruritus has been noted in recent clinical case series and case reports. This could be a milestone in treating different forms of pruritus, including drug-induced pruritus, paraneoplastic pruritus, prurigo nodularis, cutaneous T-cell lymphoma and atopic dermatitis.

Keywords

Antagonist Neurokinin-1 receptor Neuropeptides Pruritus Prurigo nodularis Substance P Aprepitant Antipruritic therapy 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Patacchini R, Lecci A, Holzer P, Maggi CA. Newly discovered tachykinins raise new questions about their peripheral roles and the tachykinin nomenclature. Trends Pharmacol Sci. 2004;25:1–3.CrossRefPubMedGoogle Scholar
  2. 2.
    Datar P, Srivastava S, Coutinho E, Govil G. Substance P: structure, function, and therapeutics. Curr Top Med Chem. 2004;4:75–103.CrossRefPubMedGoogle Scholar
  3. 3.
    Harmar AJ, Armstrong A, Pascall JC, Chapman K, Rosie R, Curtis A, Going J, Edwards CRW, Fink G. cDNA sequence of human beta-preprotachykinin, the common precursor to substance P and neurokinin A. FEBS Lett. 1986;208:67–72.CrossRefPubMedGoogle Scholar
  4. 4.
    Scholzen T, Armstrong CA, Bunnett NW, Luger TA, Olerud JE, Ansel JC. Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune systems. Exp Dermatol. 1998;272:81–96.CrossRefGoogle Scholar
  5. 5.
    Southwell BR, Seybold VS, Woodman HL, Jenkinson KM, Furness JB. Quantitation of neurokinin 1 receptor internalization and recycling in guinea-pig myenteric neurons. Neuroscience. 1998;87:925–31.CrossRefPubMedGoogle Scholar
  6. 6.
    Carstens EE, Carstens MI, Simons CT, Jinks SL. Dorsal horn neurons expressing NK-1 receptors mediate scratching in rats. Neuroreport. 2010;21:303–8.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Akiyama T, Tominaga M, Davoodi A, Nagamine M, Blansit K, Horwitz A, Carstens MI, Carstens E. Roles for substance P and gastrin-releasing peptide as neurotransmitters released by primary afferent pruriceptors. J Neurophysiol. 2013;109:742–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Saeed AW, Ribeiro-da-Silva A. De novo expression of neurokinin-1 receptors by spinoparabrachial lamina I pyramidal neurons following a peripheral nerve lesion. J Comp Neurol. 2013;521:1915–28.CrossRefPubMedGoogle Scholar
  9. 9.
    Orel M, Padrós E, Manyosa J. Structural features of the C-terminus from the human neurokinin-1 receptor. FEBS J. 2012;279(13):2357–67.CrossRefPubMedGoogle Scholar
  10. 10.
    DeVane CL. Substance P: a new era, a new role. Pharmacotherapy. 2001;21:1061–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Sahbaie P, Shi X, Guo TZ, Qiao Y, Yeomans DC, Kingery WS, Clark JD. Role of substance P signaling in enhanced nociceptive sensitization and local cytokine production after incision. Pain. 2009;145:341–9.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Takeda M, Takahashi M, Matsumoto S. Suppression of neurokinin-1 receptor in trigeminal ganglia attenuates central sensitization following inflammation. J Peripher Nerv Syst. 2012;17:169–81.CrossRefPubMedGoogle Scholar
  13. 13.
    Teodoro FC, Tronco Júnior MF, Zampronio AR, Martini AC, Rae GA, Chichorro JG. Peripheral substance P and neurokinin-1 receptors have a role in inflammatory and neuropathic orofacial pain models. Neuropeptides. 2013;47:199–206.CrossRefPubMedGoogle Scholar
  14. 14.
    Li WW, Guo TZ, Liang DY, Sun Y, Kingery WS, Clark JD. Substance P signaling controls mast cell activation, degranulation, and nociceptive sensitization in a rat fracture model of complex regional pain syndrome. Anesthesiology. 2012;116:882–95.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Weidner C, Klede M, Rukwied R, Lischetzki G, Neisius U, Skov PS, Petersen LJ, Schmelz M. Acute effects of substance P and calcitonin gene-related peptide in human skin – a microdialysis study. J Invest Dermatol. 2000;115:1015–20.CrossRefPubMedGoogle Scholar
  16. 16.
    Hägermark O, Hökfelt T, Pernow B. Flare and itch induced by substance P in human skin. J Invest Dermatol. 1978;71:233–5.CrossRefPubMedGoogle Scholar
  17. 17.
    Andoh T, Nagasawa T, Satoh M, Kuraishi Y. Substance P induction of itch-associated response mediated by cutaneous NK1 tachykinin receptors in mice. J Pharmacol Exp Ther. 1998;286:1140–5.PubMedGoogle Scholar
  18. 18.
    Kawana S, Liang Z, Nagano M, Suzuki H. Role of substance P in stress-derived degranulation of dermal mast cells in mice. J Dermatol Sci. 2006;42:47–54.CrossRefPubMedGoogle Scholar
  19. 19.
    Ikoma A, Steinhoff M, Ständer S, Yosipovitch G, Schmelz M. The neurobiology of itch. Nat Rev Neurosci. 2006;7:535–47.CrossRefPubMedGoogle Scholar
  20. 20.
    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.CrossRefPubMedGoogle Scholar
  21. 21.
    Amatya B, Nordlind K, Wahlgren CF. Responses to intradermal injections of substance P in psoriasis patients with pruritus. Skin Pharmacol Physiol. 2010;23:133–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Tanaka T, Danno K, Ikai K, Imamura S. Effects of substance P and substance K on the growth of cultured keratinocytes. J Invest Dermatol. 1988;90:399–401.CrossRefPubMedGoogle Scholar
  23. 23.
    Kähler CM, Sitte BA, Reinisch N, Wiedermann CJ. Stimulation of the chemotactic migration of human fibroblasts by substance P. Eur J Pharmacol. 1993;249:281–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Liu JY, Zhao YZ, Peng C, Li FQ, Zhu QG, Hu JH. Effect of cetirizine hydrochloride on the expression of substance P receptor and cytokines production in human epidermal keratinocytes and dermal fibroblasts. Yao Xue Xue Bao. 2008;43:383–7.PubMedGoogle Scholar
  25. 25.
    Burbach GJ, Kim KH, Zivony AS, Kim A, Aranda J, Wright S, Naik SM, Caughman SW, Ansel JC, Armstrong CA. The neurosensory tachykinins substance P and neurokinin A directly induce keratinocyte nerve growth factor. J Invest Dermatol. 2001;117:1075–82.CrossRefPubMedGoogle Scholar
  26. 26.
    Andoh T, Katsube N, Maruyama M, Kuraishi Y. Involvement of leukotriene B(4) in substance P-induced itch-associated response in mice. J Invest Dermatol. 2001;117:1621–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Andoh T, Kuraishi Y. Inhibitory effects of azelastine on substance P-induced itch-associated response in mice. Eur J Pharmacol. 2002;436:235–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Scholzen TE, Steinhoff M, Sindrilaru A, Schwarz A, Bunnett NW, Luger TA, Armstrong CA, Ansel JC. Cutaneous allergic contact dermatitis responses are diminished in mice deficient in neurokinin 1 receptors and augmented by neurokinin 2 receptor blockage. FASEB J. 2004;18:1007–9.PubMedGoogle Scholar
  29. 29.
    Scholzen TE, Ständer S, Riemann H, Brzoska T, Luger TA. Modulation of cutaneous inflammation by angiotensin-converting enzyme. J Immunol. 2003;170:3866–73.CrossRefPubMedGoogle Scholar
  30. 30.
    Abadía Molina F, Burrows NP, Jones RR, Terenghi G, Polak JM. Increased sensory neuropeptides in nodular prurigo: a quantitative immunohistochemical analysis. Br J Dermatol. 1992;127:344–51.CrossRefPubMedGoogle Scholar
  31. 31.
    Järvikallio A, Harvima IT, Naukkarinen A. Mast cells, nerves and neuropeptides in atopic dermatitis and nummular eczema. Arch Dermatol Res. 2003;295:2–7.PubMedGoogle Scholar
  32. 32.
    Haas S, Capellino S, Phan NQ, Böhm M, Luger TA, Straub RH, Ständer S. Low density of sympathetic nerve fibers relative to substance P-positive nerve fibers in lesional skin of chronic pruritus and prurigo nodularis. J Dermatol Sci. 2010;58:193–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Nakamura M, Toyoda M, Morohashi M. Pruritogenic mediators in psoriasis vulgaris: comparative evaluation of itch-associated cutaneous factors. Br J Dermatol. 2003;149:718–30.CrossRefPubMedGoogle Scholar
  34. 34.
    Chang SE, Han SS, Jung HJ, Choi JH. Neuropeptides and their receptors in psoriatic skin in relation to pruritus. Br J Dermatol. 2007;156:1272–7.CrossRefPubMedGoogle Scholar
  35. 35.
    Hosokawa C, Takeuchi S, Furue M. Severity scores, itch scores and plasma substance P levels in atopic dermatitis treated with standard topical therapy with oral olopatadine hydrochloride. J Dermatol. 2009;36:185–90.CrossRefPubMedGoogle Scholar
  36. 36.
    Trivedi M, Bergasa NV. Serum concentrations of substance P in cholestasis. Ann Hepatol. 2010;9:177–80.PubMedGoogle Scholar
  37. 37.
    Ohmura T, Hayashi T, Satoh Y, Konomi A, Jung B, Satoh H. Involvement of substance P in scratching behaviour in an atopic dermatitis model. Eur J Pharmacol. 2004;491:191–4.CrossRefPubMedGoogle Scholar
  38. 38.
    Inagaki N, Shiraishi N, Igeta K, Nagao M, Kim JF, Chikumoto T, Itoh T, Katoh H, Tanaka H, Nagai H. Depletion of substance P, a mechanism for inhibition of mouse scratching behavior by tacrolimus. Eur J Pharmacol. 2010;626:283–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Lee JH, Cho SH. Korean red ginseng extract ameliorates skin lesions in NC/Nga mice: an atopic dermatitis model. J Ethnopharmacol. 2011;133:810–7.CrossRefPubMedGoogle Scholar
  40. 40.
    Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G, Snavely D, Wyatt-Knowles E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harrison T, Hill RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith D, Carlson EJ, Hargreaves RJ, Rupniak NM. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science. 1998;281:1640–5.CrossRefPubMedGoogle Scholar
  41. 41.
    Hesketh PJ, Grunberg SM, Gralla RJ, Warr DG, Roila F, de Wit R, Chawla SP, Carides AD, Ianus J, Elmer ME, Evans JK, Beck K, Reines S, Horgan KJ, Aprepitant Protocol 052 Study Group. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin – the Aprepitant Protocol 052 Study Group. J Clin Oncol. 2003;21:4077–80.CrossRefGoogle Scholar
  42. 42.
    Dando TM, Perry C. Aprepitant: a review of its use in the prevention of chemotherapy-induced nausea and vomiting. Drugs. 2004;64:777–94.CrossRefPubMedGoogle Scholar
  43. 43.
    Jiménez Gallo D, Albarrán Planelles C, Linares Barrios M, Fernández Anguita MJ, Márquez Enríquez J, Rodríguez Mateos ME. Treatment of pruritus in early-stage hypopigmented mycosis fungoides with aprepitant. Dermatol Ther. 2014;27:178–82.CrossRefPubMedGoogle Scholar
  44. 44.
    Borja-Consigliere HA, López-Pestaña A, Vidal-Manceñido MJ, Tuneu-Valls A. Aprepitant in the treatment of refractory pruritus secondary to cutaneous T-cell lymphoma. Actas Dermosifiliogr. 2014;105:716–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Torres T, Fernandes I, Selores M, Alves R, Lima M. Aprepitant: evidence of its effectiveness in patients with refractory pruritus continues. J Am Acad Dermatol. 2012;66:e14–5.CrossRefPubMedGoogle Scholar
  46. 46.
    Booken N, Heck M, Nicolay JP, Klemke CD, Goerdt S, Utikal J. Oral aprepitant in the therapy of refractory pruritus in erythrodermic cutaneous T-cell lymphoma. Br J Dermatol. 2011;164:665–7.PubMedGoogle Scholar
  47. 47.
    Duval A, Dubertret L. Aprepitant as an antipruritic agent? N Engl J Med. 2009;361:1415–6.CrossRefPubMedGoogle Scholar
  48. 48.
    Villafranca JJ, Siles MG, Casanova M, Goitia BT, Domínguez AR. Paraneoplastic pruritus presenting with Hodgkin’s lymphoma: a case report. J Med Case Rep. 2014;8:300.CrossRefPubMedGoogle Scholar
  49. 49.
    Vincenzi B, Fratto ME, Santini D, Tonini G. Aprepitant against pruritus in patients with solid tumours. Support Care Cancer. 2010;18:1229–30.CrossRefPubMedGoogle Scholar
  50. 50.
    Santini D, Vincenzi B, Guida FM, Imperatori M, Schiavon G, Venditti O, Frezza AM, Berti P, Tonini G. Aprepitant for management of severe pruritus related to biological cancer treatments: a pilot study. Lancet Oncol. 2012;13:1020–4.CrossRefPubMedGoogle Scholar
  51. 51.
    Mir O, Blanchet B, Goldwasser F. More on aprepitant for erlotinib-induced pruritus. N Engl J Med. 2011;364:487.PubMedGoogle Scholar
  52. 52.
    Vincenzi B, Tonini G, Santini D. Aprepitant for erlotinib-induced pruritus. N Engl J Med. 2010;363:397–8.CrossRefPubMedGoogle Scholar
  53. 53.
    Ally MS, Gamba CS, Peng DH, Tang JY. The use of aprepitant in brachioradial pruritus. JAMA Dermatol. 2013;149:627–8.CrossRefPubMedGoogle Scholar
  54. 54.
    Zeidler C, Luger T, Ständer S. Antipruritic efficacy of aprepitant in non-atopic pruritus. J Dtsch Dermatol Ges. 2013;11:171.Google Scholar
  55. 55.
    Ständer S, Siepmann D, Herrgott I, Sunderkötter C, Luger TA. Targeting the neurokinin receptor 1 with aprepitant: a novel antipruritic strategy. PLoS One. 2010;5:e10968.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Ständer S, Siepmann D, Luger TA. Targeting the neurokinin receptor 1 as a new antipruritic strategy: results of a case series with aprepitant. Acta Derm Venereol. 2009;89:717.CrossRefGoogle Scholar
  57. 57.
    Ständer S, Luger TA. NK-1 antagonists and itch. Handb Exp Pharmacol. 2015;226:237–55.CrossRefPubMedGoogle Scholar
  58. 58.
    Shadle CR, Lee Y, Majumdar AK, Petty KJ, Gargano C, Bradstreet TE, Evans JK, Blum RA. Evaluation of potential inductive effects of aprepitant on cytochrome P450 3A4 and 2C9 activity. J Clin Pharmacol. 2004;44:215–23.CrossRefPubMedGoogle Scholar
  59. 59.
    Ruhlmann CH, Herrstedt J. Safety evaluation of aprepitant for the prevention of chemotherapy-induced nausea and vomiting. Expert Opin Drug Saf. 2011;10:449–62.CrossRefPubMedGoogle Scholar
  60. 60.
    Levêque D. Aprepitant for erlotinib-induced pruritus. N Engl J Med. 2010;363:1680–1.CrossRefPubMedGoogle Scholar
  61. 61.
    Mir O, Coriat R. Aprepitant for pruritus: drug-drug interactions matter. Lancet Oncol. 2012;13:964–5.CrossRefPubMedGoogle Scholar
  62. 62.
    Green SA, Alon A, Ianus J, McNaughton KS, Tozzi CA, Reiss TF. Efficacy and safety of a neurokinin-1 receptor antagonist in postmenopausal women with overactive bladder with urge urinary incontinence. J Urol. 2006;176:2535–40.CrossRefPubMedGoogle Scholar
  63. 63.
    Tebas P, Tuluc F, Barrett JS, Wagner W, Kim D, Zhao H, Gonin R, Korelitz J, Douglas SD. A randomized, placebo controlled, double masked phase IB study evaluating the safety and antiviral activity of aprepitant, a neurokinin-1 receptor antagonist in HIV-1 infected adults. PLoS One. 2011;6:e24180.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Keller M, Montgomery S, Ball W, Morrison M, Snavely D, Liu G, Hargreaves R, Hietala J, Lines C, Beebe K, Reines S. Lack of efficacy of the substance p (neurokinin1 receptor) antagonist aprepitant in the treatment of major depressive disorder. Biol Psychiatry. 2006;59:216–23.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag London 2016

Authors and Affiliations

  1. 1.Center for Chronic Pruritus (KCP), Department of DermatologyUniversity Hospital MünsterMünsterGermany

Personalised recommendations