Pruritus pp 33-38 | Cite as

Interaction of Pruritus and Pain

  • Martin SchmelzEmail author


Painful stimuli such as scratching suppresses itch and analgesic therapy with opioids induces itch. Thus, there is a general antagonistic interaction between itch and pain. Accordingly, separate specific pathways for itch and pain have been found that are identified by characteristic molecular markers. Such dichotomy would suggest that for diagnostic and therapeutic purposes itch and pain pathways have to be regarded separately. However, not only do mediators of itch and pain overlap massively, but there is also evidence that there is overlap in neuronal mechanisms of neuropathic itch and pain. Moreover, inhibitory glycinergic interneurons have been identified in the spinal cord that suppress both, nociceptive and pruriceptive processing indicating synergetic elements that coexist with antagonistic spinal pathways. Clinical and basic research concepts of chronic itch should therefore include mechanisms that are common in peripheral and central processing of nociceptors and pruriceptors.


Specificity Intensity theory Pattern theory Spontaneous discharge Neuropathy Neuropathic pain Inhibitory control Scratching Opioids Capsaicin 


  1. 1.
    Gibson PG. Cough is an airway itch? Am J Respir Crit Care Med. 2004;169(1):1–2. doi: 10.1164/rccm.2310009.CrossRefPubMedGoogle Scholar
  2. 2.
    Akiyama T, Carstens E. Neural processing of itch. Neuroscience. 2013;250:697–714. doi: 10.1016/j.neuroscience.2013.07.035.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    LaMotte RH, Dong X, Ringkamp M. Sensory neurons and circuits mediating itch. Nat Rev Neurosci. 2014;15(1):19–31. doi: 10.1038/nrn3641.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bautista DM, Wilson SR, Hoon MA. Why we scratch an itch: the molecules, cells and circuits of itch. Nat Neurosci. 2014;17(2):175–82. doi: 10.1038/nn.3619.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Braz J, Solorzano C, Wang X, Basbaum AI. Transmitting pain and itch messages: a contemporary view of the spinal cord circuits that generate gate control. Neuron. 2014;82(3):522–36. doi: 10.1016/j.neuron.2014.01.018.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ackerley R, Backlund Wasling H, Liljencrantz J, Olausson H, Johnson RD, Wessberg J. Human C-tactile afferents are tuned to the temperature of a skin-stroking caress. J Neurosci. 2014;34(8):2879–83. doi: 10.1523/JNEUROSCI.2847-13.2014.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Vrontou S, Wong AM, Rau KK, Koerber HR, Anderson DJ. Genetic identification of C fibres that detect massage-like stroking of hairy skin in vivo. Nature. 2013;493(7434):669–73.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Seal RP, Wang X, Guan Y, Raja SN, Woodbury CJ, Basbaum AI, Edwards RH. Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors. Nature. 2009;462(7273):651–5.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    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(17):4331–5. doi: 10.1523/JNEUROSCI.0716-08.2008[doi]. 28/17/4331 [pii].CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Johanek LM, Meyer RA, Friedman RM, Greenquist KW, Shim B, Borzan J, Hartke T, LaMotte RH, Ringkamp M. A role for polymodal C-fiber afferents in nonhistaminergic itch. J Neurosci. 2008;28(30):7659–69.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Qu L, Fan N, Ma C, Wang T, Han L, Fu K, Wang Y, Shimada SG, Dong X, Lamotte RH. Enhanced excitability of MRGPRA3- and MRGPRD-positive nociceptors in a model of inflammatory itch and pain. Brain. 2014. doi: 10.1093/brain/awu007.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Han L, Ma C, Liu Q, Weng HJ, Cui Y, Tang Z, Kim Y, Nie H, Qu L, Patel KN, Li Z, McNeil B, He S, Guan Y, Xiao B, LaMotte RH, Dong X. A subpopulation of nociceptors specifically linked to itch. Nat Neurosci. 2012;16(2):174–82.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Liu Q, Sikand P, Ma C, Tang Z, Han L, Li Z, Sun S, LaMotte RH, Dong X. Mechanisms of itch evoked by beta-alanine. J Neurosci. 2012;32(42):14532–7.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Wooten M, Weng HJ, Hartke TV, Borzan J, Klein AH, Turnquist B, Dong X, Meyer RA, Ringkamp M. Three functionally distinct classes of C-fibre nociceptors in primates. Nat Commun. 2014;5:4122. doi: 10.1038/ncomms5122.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Sikand P, Dong X, LaMotte RH. BAM8-22 peptide produces itch and nociceptive sensations in humans independent of histamine release. J Neurosci. 2011;31(20):7563–7. doi: 10.1523/JNEUROSCI.1192-11.2011[doi]. 31/20/7563 [pii].CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Nilsson HJ, Levinsson A, Schouenborg J. Cutaneous field stimulation (CFS): a new powerful method to combat itch. Pain. 1997;71(1):49–55.CrossRefPubMedGoogle Scholar
  17. 17.
    Brull SJ, Atanassoff PG, Silverman DG, Zhang J, LaMotte RH. Attenuation of experimental pruritus and mechanically evoked dysesthesiae in an area of cutaneous allodynia. Somatosens Mot Res. 1999;16(4):299–303.CrossRefPubMedGoogle Scholar
  18. 18.
    Simone DA, Nolano M, Johnson T, Wendelschafer-Crabb G, Kennedy WR. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: correlation with sensory function. J Neurosci. 1998;18(21):8947–54.PubMedGoogle Scholar
  19. 19.
    Atanassoff PG, Brull SJ, Zhang J, Greenquist K, Silverman DG, LaMotte RH. Enhancement of experimental pruritus and mechanically evoked dysesthesiae with local anesthesia. Somatosens Mot Res. 1999;16(4):291–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Andrew D, Schmelz M, Ballantyne JC. Itch – mechanisms and mediators. In: Dostrovsky JO, Carr DB, Koltzenburg M, editors. Progress in pain research and management, vol. 24. Seattle: IASP Press; 2003. p. 213–26.Google Scholar
  21. 21.
    Nojima H, Cuellar JM, Simons CT, Carstens MI, Carstens E. Spinal c-fos expression associated with spontaneous biting in a mouse model of dry skin pruritus. Neurosci Lett. 2004;361(1–3):79–82.CrossRefPubMedGoogle Scholar
  22. 22.
    Ross SE, Mardinly AR, McCord AE, Zurawski J, Cohen S, Jung C, Hu L, Mok SI, Shah A, Savner EM, Tolias C, Corfas R, Chen S, Inquimbert P, Xu Y, McInnes RR, Rice FL, Corfas G, Ma Q, Woolf CJ, Greenberg ME. Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron. 2010;65(6):886–98.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Braz JM, Juarez-Salinas D, Ross SE, Basbaum AI. Transplant restoration of spinal cord inhibitory controls ameliorates neuropathic itch. J Clin Invest. 2014;124(8):3612–6. doi: 10.1172/JCI75214.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kardon AP, Polgar E, Hachisuka J, Snyder LM, Cameron D, Savage S, Cai X, Karnup S, Fan CR, Hemenway GM, Bernard CS, Schwartz ES, Nagase H, Schwarzer C, Watanabe M, Furuta T, Kaneko T, Koerber HR, Todd AJ, Ross SE. Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord. Neuron. 2014;82(3):573–86. doi: 10.1016/j.neuron.2014.02.046.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Foster E, Wildner H, Tudeau L, Haueter S, Ralvenius WT, Jegen M, Johannssen H, Hosli L, Haenraets K, Ghanem A, Conzelmann KK, Bosl M, Zeilhofer HU. Targeted ablation, silencing, and activation establish glycinergic dorsal horn neurons as key components of a spinal gate for pain and itch. Neuron. 2015;85(6):1289–304. doi: 10.1016/j.neuron.2015.02.028.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Bromm B, Scharein E, Darsow U, Ring J. Effects of menthol and cold on histamine-induced itch and skin reactions in man. Neurosci Lett. 1995;187(3):157–60.CrossRefPubMedGoogle Scholar
  27. 27.
    Mizumura K, Koda H. Potentiation and suppression of the histamine response by raising and lowering the temperature in canine visceral polymodal receptors in vitro. Neurosci Lett. 1999;266(1):9–12.CrossRefPubMedGoogle Scholar
  28. 28.
    Heyer G, Ulmer FJ, Schmitz J, Handwerker HO. Histamine-induced itch and alloknesis (itchy skin) in atopic eczema patients and controls. Acta Derm Venereol (Stockh). 1995;75(5):348–52.Google Scholar
  29. 29.
    Pfab F, Valet M, Sprenger T, Toelle TR, Athanasiadis GI, Behrendt H, Ring J, Darsow U. Short-term alternating temperature enhances histamine-induced itch: a biphasic stimulus model. J Invest Dermatol. 2006;126(12):2673–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Napadow V, Li A, Loggia ML, Kim J, Schalock PC, Lerner E, Tran TN, Ring J, Rosen BR, Kaptchuk TJ, Pfab F. The brain circuitry mediating antipruritic effects of acupuncture. Cereb Cortex. 2014;24(4):873–82. doi: 10.1093/cercor/bhs363.CrossRefPubMedGoogle Scholar
  31. 31.
    Schmelz M. Itch – mediators and mechanisms. J Dermatol Sci. 2002;28(2):91–6.CrossRefPubMedGoogle Scholar
  32. 32.
    LaMotte RH, Shain CN, Simone DA, Tsai EFP. Neurogenic hyperalgesia psychophysical studies of underlying mechanisms. J Neurophysiol. 1991;66:190–211.PubMedGoogle Scholar
  33. 33.
    Bickford RGL. Experiments relating to itch sensation, its peripheral mechanism and central pathways. Clin Sci. 1938;3:377–86.Google Scholar
  34. 34.
    Simone DA, Alreja M, LaMotte RH. Psychophysical studies of the itch sensation and itchy skin (“alloknesis”) produced by intracutaneous injection of histamine. Somatosens Mot Res. 1991;8(3):271–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Namer B, Reeh P. Scratching an itch. Nat Neurosci. 2013;16(2):117–8. doi: 10.1038/nn.3316.CrossRefPubMedGoogle Scholar
  36. 36.
    Handwerker HO. Itch hypotheses: from pattern to specificity and to population coding. In: Carstens E, Akiyama T, editors. Itch: mechanisms and treatment. Frontiers in neuroscience. Boca Raton: CRC Press; 2014.Google Scholar
  37. 37.
    LaMotte RH, Shimada SG, Green BG, Zelterman D. Pruritic and nociceptive sensations and dysesthesias from a spicule of cowhage. J Neurophysiol. 2009;101(3):1430–43. doi: 10.1152/jn.91268.2008[doi]. 91268.2008 [pii].CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    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(1–2):66–75.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Johanek LM, Meyer RA, Hartke T, Hobelmann JG, Maine DN, LaMotte RH, Ringkamp M. Psychophysical and physiological evidence for parallel afferent pathways mediating the sensation of itch. J Neurosci. 2007;27(28):7490–7.CrossRefPubMedGoogle Scholar
  40. 40.
    Schmidt R, Schmelz M, Forster C, Ringkamp M, Torebjörk HE, Handwerker HO. Novel classes of responsive and unresponsive C nociceptors in human skin. J Neurosci. 1995;15(1 Pt 1):333–41.PubMedGoogle Scholar
  41. 41.
    Tuckett RP, Wei JY. Response to an itch-producing substance in cat. II. Cutaneous receptor populations with unmyelinated axons. Brain Res. 1987;413(1):95–103.CrossRefPubMedGoogle Scholar
  42. 42.
    Namer B, Carr R, Johanek LM, Schmelz M, Handwerker HO, Ringkamp M. Separate peripheral pathways for pruritus in man. J Neurophysiol. 2008;100(4):2062–9.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    McMahon SB, Koltzenburg M. Itching for an explanation. Trends Neurosci. 1992;15(12):497–501.CrossRefPubMedGoogle Scholar
  44. 44.
    Schmelz M, Handwerker HO. Itch, vol 6. Wall & Melzack’s textbook of pain. Philadelphia: Elsevier; 2013.Google Scholar
  45. 45.
    Oaklander AL, Bowsher D, Galer B, Haanpää M, Jensen MP. Herpes zoster itch: preliminary epidemiologic data. J Pain. 2003;4(6):338–43.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag London 2016

Authors and Affiliations

  1. 1.Department of Anesthesiology and Intensive Care Medicine, Medical Faculty MannheimHeidelberg UniversityMannheimGermany

Personalised recommendations