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  • Review Article
  • Published:

The neurobiology of itch

Nature Reviews Neuroscience volume 7, pages 535–547 (2006)Cite this article

Key Points

  • The mechanisms of chronic itch conditions have yet to be fully clarified, and therefore itch is clinically classified according to the underlying diseases originating in the skin, which are either systemic or directly damage neurons.

  • Antagonistic interactions between itch and pain underlie the suppression of itch by inducing pain through scratching, but also itch that is evoked by opioid analgesics. Therapeutically, opioid antagonists have shown antipruritic efficacy.

  • Similar patterns of peripheral neuronal sensitization and nerve fibre sprouting have been found in both chronic itch and chronic pain conditions. Nerve growth factor (NGF) has emerged as a possible underlying mediator. Therefore, anti-NGF strategies are promising as antipruritic and analgesic therapies.

  • Symptoms of central sensitization are strikingly similar between itch (allodynia versus punctate hyperalgesia) and pain (alloknesis versus punctate hyperknesis). The antipruritic efficacy of classical analgesics for neuropathic pain (for example, gabapentin and antidepressants) also suggests common underlying mechanisms for neuropathic pain and itch.

  • A broad overlap of receptor systems exists between pain and itch, including protease-activated receptors (PARs) and transient receptor potential receptor vanilloid type 1 (TRPV1). Apart from histamine H1 receptors, new candidates for pruritus-specific mediator systems are interleukin-31 and H4 receptors.

  • Keratinocytes might contribute to pruritus not only by releasing sensitizing mediators, such as NGF, but also through their involvement in the transduction process through their TRPV1, TRPV3 and TRPV4 receptors.

  • A distinct neuronal pathway for itch consisting of histamine-sensitive mechano-insensitive primary afferent C-fibres and spino-thalamic projection neurons has been identified that can explain some, but not all, subtypes of itch. Mechanically-, electrically- or cowhage-induced itch is not mediated by this fibre class, which indicates the existence of additional, as yet to be characterized, pruriceptive nerve fibre classes.

  • Central imaging has identified similar areas as being involved in acute itch and pain processing, including the dorsal posterior insula, anterior cingulated and prefrontal cortices, as well as the thalamus and premotor areas. More pronounced ipsilateral activation of motor areas in itch might relate to the planning of a scratch response.

  • Clinically important, itch not only has aversive dimensions, but also has a hedonic component, which might be a key driver for compulsive scratching.

Abstract

The neurobiology of itch, which is formally known as pruritus, and its interaction with pain have been illustrated by the complexity of specific mediators, itch-related neuronal pathways and the central processing of itch. Scratch-induced pain can abolish itch, and analgesic opioids can generate itch, which indicates an antagonistic interaction. However, recent data suggest that there is a broad overlap between pain- and itch-related peripheral mediators and/or receptors, and there are astonishingly similar mechanisms of neuronal sensitization in the PNS and the CNS. The antagonistic interaction between pain and itch is already exploited in pruritus therapy, and current research concentrates on the identification of common targets for future analgesic and antipruritic therapy.

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Figure 1: Mediators and the sensitization pattern of nociceptive and pruriceptive neurons.
Figure 2: Activation patterns of primary afferent fibres and spinal projection neurons in response to itch or pain sensation evoked by iontophoresis of histamine.
Figure 3: Activated brain areas in pain and itch as assessed by central imaging.

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References

  1. v.Frey, M. Zur Physiologie der Juckempfindung. Arch. Neerl. Physiol. 7, 142–145 (1922).

    Google Scholar 

  2. Nojima, H. et al. Opioid modulation of scratching and spinal c-fos expression evoked by intradermal serotonin. J. Neurosci. 23, 10784–10790 (2003). c-Fos expression as objective evidence for differential pain and itch behaviour in animals.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Schmelz, M., Schmidt, R., Bickel, A., Handwerker, H. O. & Torebjörk, H. E. Specific C-receptors for itch in human skin. J. Neurosci. 17, 8003–8008 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Andrew, D. & Craig, A. D. Spinothalamic lamina 1 neurons selectively sensitive to histamine: a central neural pathway for itch. Nature Neurosci. 4, 72–77 (2001). References 3 and 4 are pioneering works on the identification of an itch-selective neuronal pathway.

    CAS  PubMed  Google Scholar 

  5. McMahon, S. B. & Koltzenburg, M. Itching for an explanation. Trends. Neurosci. 15, 497–501 (1992).

    CAS  PubMed  Google Scholar 

  6. Twycross, R. et al. Itch: scratching more than the surface. QJM. 96, 7–26 (2003).

    CAS  PubMed  Google Scholar 

  7. Bernhard, J. D. Itch and pruritus: what are they, and how should itches be classified? Dermatol. Ther. 18, 288–291 (2005).

    PubMed  Google Scholar 

  8. Ward, L., Wright, E. & McMahon, S. B. A comparison of the effects of noxious and innocuous counterstimuli on experimentally induced itch and pain. Pain 64, 129–138 (1996).

    CAS  PubMed  Google Scholar 

  9. Nilsson, H. J., Levinsson, A. & Schouenborg, J. Cutaneous field stimulation (CFS): a new powerful method to combat itch. Pain 71, 49–55 (1997).

    CAS  PubMed  Google Scholar 

  10. Yosipovitch, G., Fast, K. & Bernhard, J. D. Noxious heat and scratching decrease histamine-induced itch and skin blood flow. J. Invest. Dermatol. 125, 1268–1272 (2005).

    CAS  PubMed  Google Scholar 

  11. Brull, S. J., Atanassoff, P. G., Silverman, D. G., Zhang, J. & LaMotte, R. H. Attenuation of experimental pruritus and mechanically evoked dysesthesiae in an area of cutaneous allodynia. Somatosens. Mot. Res. 16, 299–303 (1999).

    CAS  PubMed  Google Scholar 

  12. Green, A. D., Young, K. K., Lehto, S. G., Smith, S. B. & Mogil, J. S. Influence of genotype, dose and sex on pruritogen-induced scratching behaviour in the mouse. Pain 10 May 2006 (doi:10.1016/j.pain.2006.03.023). Pioneering work on the genetic approach to itch research.

  13. Mogil, J. S. et al. Variable sensitivity to noxious heat is mediated by differential expression of the CGRP gene. Proc. Natl Acad. Sci. USA 102, 12938–12943 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Atanassoff, P. G. et al. Enhancement of experimental pruritus and mechanically evoked dysesthesiae with local anesthesia. Somatosens. Mot. Res. 16, 291–298 (1999).

    CAS  PubMed  Google Scholar 

  15. Andrew, D., Schmelz, M. & Ballantyne, J. C. in Progress in Pain Research and Management (eds Dostrovsky, J. O., Carr, D. B. & Koltzenburg, M.) 213–226 (IASP Press, Seattle, 2003).

    Google Scholar 

  16. Heyer, G., Dotzer, M., Diepgen, T. L. & Handwerker, H. O. Opiate and H1 antagonist effects on histamine induced pruritus and alloknesis. Pain 73, 239–243 (1997).

    CAS  PubMed  Google Scholar 

  17. Ko, M. C., Song, M. S., Edwards, T., Lee, H. & Naughton, N. N. The role of central μ opioid receptors in opioid-induced itch in primates. J. Pharmacol. Exp. Ther. 310, 169–176 (2004).

    CAS  PubMed  Google Scholar 

  18. Bergasa, N. V. The pruritus of cholestasis. J. Hepatol. 43, 1078–1088 (2005).

    PubMed  Google Scholar 

  19. McRae, C. A. et al. Pain as a complication of use of opiate antagonists for symptom control in cholestasis. Gastroenterology 125, 591–596 (2003).

    PubMed  Google Scholar 

  20. Jones, E. A., Neuberger, J. & Bergasa, N. V. Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions. QJM 95, 547–552 (2002).

    CAS  PubMed  Google Scholar 

  21. Kamei, J. & Nagase, H. Norbinaltorphimine, a selective κ-opioid receptor antagonist, induces an itch-associated response in mice. Eur. J. Pharmacol. 418, 141–145 (2001).

    CAS  PubMed  Google Scholar 

  22. Ko, M. C. et al. Activation of κ-opioid receptors inhibits pruritus evoked by subcutaneous or intrathecal administration of morphine in monkeys. J. Pharmacol. Exp. Ther. 305, 173–179 (2003).

    CAS  PubMed  Google Scholar 

  23. Wakasa, Y. et al. Inhibitory effects of TRK-820 on systemic skin scratching induced by morphine in rhesus monkeys. Life Sci. 75, 2947–2957 (2004).

    CAS  PubMed  Google Scholar 

  24. Kjellberg, F. & Tramer, M. R. Pharmacological control of opioid-induced pruritus: a quantitative systematic review of randomized trials. Eur. J. Anaesthesiol. 18, 346–357 (2001).

    CAS  PubMed  Google Scholar 

  25. Wikstrom, B. et al. κ-opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies. J. Am. Soc. Nephrol. 16, 3742–3747 (2005).

    PubMed  Google Scholar 

  26. Dawn, A. G. & Yosipovitch, G. Butorphanol for treatment of intractable pruritus. J. Am. Acad. Dermatol. 54, 527–531 (2006).

    PubMed  Google Scholar 

  27. Reeh, P. W. & Kress, M. Effects of Classical Algogens. Semin. Neurosci. 7, 221–226 (1995).

    CAS  Google Scholar 

  28. Kidd, B. L. & Urban, L. A. Mechanisms of inflammatory pain. Br. J. Anaesth. 87, 3–11 (2001).

    CAS  PubMed  Google Scholar 

  29. Zhang, X., Huang, J. & McNaughton, P. A. NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. EMBO J. 24, 4211–4223 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Hefti, F. F. et al. Novel class of pain drugs based on antagonism of NGF. Trends Pharmacol. Sci. 27, 85–91 (2005).

    PubMed  Google Scholar 

  31. Bohm-Starke, N., Hilliges, M., Falconer, C. & Rylander, E. Increased intraepithelial innervation in women with vulvar vestibulitis syndrome. Gynecol. Obstet. Invest. 46, 256–260 (1998).

    CAS  PubMed  Google Scholar 

  32. Urashima, R. & Mihara, M. Cutaneous nerves in atopic dermatitis — a histological, immunohistochemical and electron microscopic study. Virchows Arch. Int. J. Pathol. 432, 363–370 (1998).

    CAS  Google Scholar 

  33. Toyoda, M. et al. Nerve growth factor and substance P are useful plasma markers of disease activity in atopic dermatitis. Br. J. Dermatol. 147, 71–79 (2002).

    CAS  PubMed  Google Scholar 

  34. Groneberg, D. A. et al. Gene expression and regulation of nerve growth factor in atopic dermatitis mast cells and the human mast cell line-1. J. Neuroimmunol. 161, 87–92 (2005). References 33 and 34 provide convincing evidence for clinically relevant NGF increases in atopic dermatitis.

    CAS  PubMed  Google Scholar 

  35. Kinkelin, I., Motzing, S., Koltenzenburg, M. & Brocker, E. B. Increase in NGF content and nerve fiber sprouting in human allergic contact eczema. Cell Tissue Res. 302, 31–37 (2000).

    CAS  PubMed  Google Scholar 

  36. Johansson, O., Liang, Y. & Emtestam, L. Increased nerve growth factor- and tyrosine kinase A-like immunoreactivities in prurigo nodularis skin — an exploration of the cause of neurohyperplasia. Arch. Dermatol. Res. 293, 614–619 (2002).

    CAS  PubMed  Google Scholar 

  37. Choi, J. C., Yang, J. H., Chang, S. E. & Choi, J. H. Pruritus and nerve growth factor in psoriasis. Korean J. Dermatol. 43, 769–773 (2005).

    Google Scholar 

  38. Halvorson, K. G. et al. A blocking antibody to nerve growth factor attenuates skeletal pain induced by prostate tumor cells growing in bone. Cancer Res. 65, 9426–9435 (2005).

    CAS  PubMed  Google Scholar 

  39. Lane, N. et al. RN624 (Anti-NGF) improves pain and function in subjects with moderate knee osteoarthritis: a Phase I study. Osteoarthritis — clinical aspects. Proceedings American College of Rheumatology Abstr. 765 (2005).

  40. Takano, N., Sakurai, T. & Kurachi, M. Effects of anti-nerve growth factor antibody on symptoms in the NC/Nga mouse, an atopic dermatitis model. J. Pharmacol. Sci. 99, 277–286 (2005). References 39 and 40 provided the first evidence for therapeutic efficacy of anti-NGF strategies in itch and pain.

    CAS  PubMed  Google Scholar 

  41. Tanaka, A. & Matsuda, H. Expression of nerve growth factor in itchy skins of atopic NC/NgaTnd mice. J. Vet. Med. Sci. 67, 915–919 (2005).

    CAS  PubMed  Google Scholar 

  42. Verge, V. M., Richardson, P. M., Wiesenfeld-Hallin, Z. & Hokfelt, T. Differential influence of nerve growth factor on neuropeptide expression in vivo: a novel role in peptide suppression in adult sensory neurons. J. Neurosci. 15, 2081–2096 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Laird, J. M., Roza, C., De Felipe, C., Hunt, S. P. & Cervero, F. Role of central and peripheral tachykinin NK1 receptors in capsaicin-induced pain and hyperalgesia in mice. Pain 90, 97–103 (2001).

    CAS  PubMed  Google Scholar 

  44. Hill, R. NK1 (substance P) receptor antagonists — why are they not analgesic in humans? Trends Pharmacol. Sci. 21, 244–246 (2000).

    CAS  PubMed  Google Scholar 

  45. Weidner, C. et al. Acute effects of substance P and calcitonin gene-related peptide in human skin — a microdialysis study. J. Invest. Dermatol. 115, 1015–1020 (2000).

    CAS  PubMed  Google Scholar 

  46. Yosipovitch, G., Greaves, M. & Schmelz, M. Itch. Lancet 361, 690–694 (2003).

    PubMed  Google Scholar 

  47. Sun, R. Q. et al. Calcitonin gene-related peptide receptor activation produces PKA- and PKC-dependent mechanical hyperalgesia and central sensitization. J. Neurophysiol. 92, 2859–2866 (2004).

    CAS  PubMed  Google Scholar 

  48. Ekblom, A., Lundeberg, T. & Wahlgren, C. F. Influence of calcitonin gene-related peptide on histamine- and substance P-induced itch, flare and weal in humans. Skin Pharmacol. 6, 215–222 (1993).

    CAS  PubMed  Google Scholar 

  49. Katsuno, M. et al. Neuropeptides concentrations in the skin of a murine (NC/Nga mice) model of atopic dermatitis. J. Dermatol. Sci. 33, 55–65 (2003).

    CAS  PubMed  Google Scholar 

  50. Koltzenburg, M. Neural mechanisms of cutaneous nociceptive pain. Clin. J. Pain 16, S131–S138 (2000).

    CAS  PubMed  Google Scholar 

  51. Torebjörk, H. E., Schmelz, M. & Handwerker, H. O. Functional properties of human cutaneous nociceptors and their role in pain and hyperalgesia (eds Cervero & Belmonte, C.) 349–369 (Oxford Univ. Press, 1996).

  52. LaMotte, R. H., Shain, C. N., Simone, D. A. & Tsai, E. F. P. Neurogenic hyperalgesia psychophysical studies of underlying mechanisms. J. Neurophysiol. 66, 190–211 (1991).

    CAS  PubMed  Google Scholar 

  53. Bickford, R. G. L. Experiments relating to itch sensation, its peripheral mechanism and central pathways. Clin. Sci. 3, 377–386 (1938).

    Google Scholar 

  54. Simone, D. A., Alreja, M. & LaMotte, R. H. Psychophysical studies of the itch sensation and itchy skin ('alloknesis') produced by intracutaneous injection of histamine. Somatosens. Mot. Res. 8, 271–279 (1991). A detailed psychophysical investigation of central sensitization for itch.

    CAS  PubMed  Google Scholar 

  55. Heyer, G., Ulmer, F. J., Schmitz, J. & Handwerker, H. O. Histamine-induced itch and alloknesis (itchy skin) in atopic eczema patients and controls. Acta Derm. Venereol. (Stockh.) 75, 348–352 (1995).

    CAS  Google Scholar 

  56. Nilsson, H. J. & Schouenborg, J. Differential inhibitory effect on human nociceptive skin senses induced by local stimulation of thin cutaneous fibers. Pain 80, 103–112 (1999).

    CAS  PubMed  Google Scholar 

  57. Vogelsang, M., Heyer, G. & Hornstein, O. P. Acetylcholine induces different cutaneous sensations in atopic and non-atopic subjects. Acta Derm. Venereol. 75, 434–436 (1995).

    CAS  PubMed  Google Scholar 

  58. Birklein, F., Claus, D., Riedl, B., Neundorfer, B. & Handwerker, H. O. Effects of cutaneous histamine application in patients with sympathetic reflex dystrophy. Muscle Nerve 20, 1389–1395 (1997).

    CAS  PubMed  Google Scholar 

  59. Baron, R., Schwarz, K., Kleinert, A., Schattschneider, J. & Wasner, G. Histamine-induced itch converts into pain in neuropathic hyperalgesia. Neuroreport 12, 3475–3478 (2001). References 58 and 59 were the first descriptions of central sensitization for normally pruritic histamine in chronic pain patients, and introduced evidence for central sensitization for C-fibre input in humans.

    CAS  PubMed  Google Scholar 

  60. Ikoma, A. et al. Painful stimuli evoke itch in patients with chronic pruritus: central sensitization for itch. Neurology 62, 212–217 (2004).

    CAS  PubMed  Google Scholar 

  61. Summey, B. T., Jr. & Yosipovitch, G. Pharmacologic advances in the systemic treatment of itch. Dermatol. Ther. 18, 328–332 (2005).

    PubMed  Google Scholar 

  62. Rogawski, M. A. & Loscher, W. The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nature Med. 10, 685–692 (2004).

    CAS  PubMed  Google Scholar 

  63. Bueller, H. A., Bernhard, J. D. & Dubroff, L. M. Gabapentin treatment for brachioradial pruritus. J. Eur. Acad. Dermatol. Venereol. 13, 227–228 (1999).

    CAS  PubMed  Google Scholar 

  64. Winhoven, S. M., Coulson, I. H. & Bottomley, W. W. Brachioradial pruritus: response to treatment with gabapentin. Br. J. Dermatol. 150, 786–787 (2004).

    CAS  PubMed  Google Scholar 

  65. Yesudian, P. D. & Wilson, N. J. Efficacy of gabapentin in the management of pruritus of unknown origin. Arch. Dermatol. 141, 1507–1509 (2005).

    CAS  PubMed  Google Scholar 

  66. Gupta, M. A. & Guptat, A. K. The use of antidepressant drugs in dermatology. J. Eur. Acad. Dermatol. Venereol. 15, 512–518 (2001).

    CAS  PubMed  Google Scholar 

  67. Zylicz, Z., Krajnik, M., Sorge, A. A. & Costantini, M. Paroxetine in the treatment of severe non-dermatological pruritus: a randomized, controlled trial. J. Pain Symptom Manage. 26, 1105–1112 (2003).

    CAS  PubMed  Google Scholar 

  68. Anttila, S. A. & Leinonen, E. V. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev. 7, 249–264 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Davis, M. P., Frandsen, J. L., Walsh, D., Andresen, S. & Taylor, S. Mirtazapine for pruritus. J. Pain Symptom Manage. 25, 288–291 (2003).

    PubMed  Google Scholar 

  70. Hundley, J. L. & Yosipovitch, G. Mirtazapine for reducing nocturnal itch in patients with chronic pruritus: a pilot study. J. Am. Acad. Dermatol. 50, 889–891 (2004).

    PubMed  Google Scholar 

  71. Bomholt, S. F., Mikkelsen, J. D. & Blackburn-Munro, G. Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain. Neuropharmacology 48, 252–263 (2005).

    CAS  PubMed  Google Scholar 

  72. Oaklander, A. L., Bowsher, D., Galer, B., Haanpää, M. & Jensen, M. P. Herpes zoster itch: preliminary epidemiologic data. J. Pain 4, 338–343 (2003).

    PubMed  Google Scholar 

  73. Morita, E., Matsuo, H. & Zhang, Y. Double-blind, crossover comparison of olopatadine and cetirizine versus placebo: suppressive effects on skin response to histamine iontophoresis. J. Dermatol. 32, 58–61 (2005).

    CAS  PubMed  Google Scholar 

  74. Klein, P. A. & Clark, R. A. An evidence-based review of the efficacy of antihistamines in relieving pruritus in atopic dermatitis. Arch. Dermatol. 135, 1522–1525 (1999).

    CAS  PubMed  Google Scholar 

  75. 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. 142, 374–380 (2004). Introduces a new and powerful candidate for an itch-specific mediator system in rodents.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Sommer, C. & Kress, M. Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci. Lett. 361, 184–187 (2004).

    CAS  PubMed  Google Scholar 

  77. Cremer, B., Heimann, A., Dippel, E. & Czarnetzki, B. M. Pruritogenic effects of mitogen stimulated peripheral blood mononuclear cells in atopic eczema. Acta Derm. Venereol. (Stockh.) 75, 426–428 (1995).

    CAS  Google Scholar 

  78. Lippert, U. et al. Role of antigen-induced cytokine release in atopic pruritus. Int. Arch. Allergy Immunol. 116, 36–39 (1998).

    CAS  PubMed  Google Scholar 

  79. Grothe, C. et al. Expression of interleukin-6 and its receptor in the sciatic nerve and cultured Schwann cells: relation to 18-kD fibroblast growth factor-2. Brain Res. 885, 172–181 (2000).

    CAS  PubMed  Google Scholar 

  80. Dillon, S. R. et al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nature Immunol. 5, 752–760 (2004). Introduces a new and powerful candidate for an itch-specific mediator system, with major implications for human diseases.

    CAS  Google Scholar 

  81. Takaoka, A. et al. Expression of IL-31 gene transcripts in NC/Nga mice with atopic dermatitis. Eur. J. Pharmacol. 516, 180–181 (2005).

    CAS  PubMed  Google Scholar 

  82. Takaoka, A. et al. Involvement of IL-31 on scratching behavior in NC/Nga mice with atopic-like dermatitis. Exp. Dermatol. 15, 161–167 (2006).

    CAS  PubMed  Google Scholar 

  83. Bilsborough, J. et al. IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis. J. Allergy Clin. Immunol. 117, 418–425 (2006).

    CAS  PubMed  Google Scholar 

  84. Biro, T. et al. How best to fight that nasty itch — from new insights into the neuroimmunological, neuroendocrine, and neurophysiological bases of pruritus to novel therapeutic approaches. Exp. Dermatol. 14, 225 (2005).

    CAS  PubMed  Google Scholar 

  85. Vergnolle, N. et al. Proteinase-activated receptor-2 and hyperalgesia: a novel pain pathway. Nature Med. 7, 821–826 (2001).

    CAS  PubMed  Google Scholar 

  86. Vergnolle, N. The enteric nervous system in inflammation and pain: the role of proteinase-activated receptors. Can. J. Gastroenterol. 17, 589–592 (2003).

    PubMed  Google Scholar 

  87. Coelho, A. M., Vergnolle, N., Guiard, B., Fioramonti, J. & Bueno, L. Proteinases and proteinase-activated receptor 2: a possible role to promote visceral hyperalgesia in rats. Gastroenterology 122, 1035–1047 (2002).

    CAS  PubMed  Google Scholar 

  88. Asfaha, S., Brussee, V., Chapman, K., Zochodne, D. W. & Vergnolle, N. Proteinase-activated receptor-1 agonists attenuate nociception in response to noxious stimuli. Br. J. Pharmacol. 135, 1101–1106 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Vergnolle, N., Wallace, J. L., Bunnett, N. W. & Hollenberg, M. D. Protease-activated receptors in inflammation, neuronal signaling and pain. Trends Pharmacol. Sci. 22, 146–152 (2001).

    CAS  PubMed  Google Scholar 

  90. Steinhoff, M. et al. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nature Med. 6, 151–158 (2000). Presents a new concept of the role of proteases in neurogenic inflammation.

    CAS  PubMed  Google Scholar 

  91. Dai, Y. et al. Proteinase-activated receptor 2-mediated potentiation of transient receptor potential vanilloid subfamily 1 activity reveals a mechanism for proteinase-induced inflammatory pain. J. Neurosci. 24, 4293–4299 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Paus, R., Schmelz, M., Biro, T. & Steinhoff, M. Scratching the brain for more effective itch therapy — frontiers in pruritus research. J. Clin. Invest. 116, 1174–1186 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 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 

  94. Narita, M. et al. Protease-activated receptor-1 and platelet-derived growth factor in spinal cord neurons are implicated in neuropathic pain after nerve injury. J. Neurosci. 25, 10000–10009 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Houle, S., Papez, M. D., Ferazzini, M., Hollenberg, M. D. & Vergnolle, N. Neutrophils and the kallikrein-kinin system in proteinase-activated receptor 4-mediated inflammation in rodents. Br. J. Pharmacol. 146, 670–678 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Bodo, E. et al. Vanilloid receptor-1 (VR1) is widely expressed on various epithelial and mesenchymal cell types of human skin. J. Invest. Dermatol. 123, 410–413 (2004).

    CAS  PubMed  Google Scholar 

  97. Inoue, K. et al. Functional vanilloid receptors in cultured normal human epidermal keratinocytes. Biochem. Biophys. Res. Commun. 291, 124–129 (2002).

    CAS  PubMed  Google Scholar 

  98. Stander, S. et al. Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures. Exp. Dermatol. 13, 129–139 (2004).

    PubMed  Google Scholar 

  99. Hwang, S. W. et al. Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc. Natl Acad. Sci. USA 97, 6155–6160 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Chuang, H. H. et al. Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4, 5)P2-mediated inhibition. Nature 411, 957–962 (2001).

    CAS  PubMed  Google Scholar 

  101. Shin, J. et al. Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia. Proc. Natl Acad. Sci. USA 99, 10150–10155 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Mohapatra, D. P. & Nau, C. Desensitization of capsaicin-activated currents in the vanilloid receptor TRPV1 is decreased by the cyclic AMP-dependent protein kinase pathway. J. Biol. Chem. 278, 50080–50090 (2003).

    CAS  PubMed  Google Scholar 

  103. Cortright, D. N. & Szallasi, A. Biochemical pharmacology of the vanilloid receptor TRPV1. An update. Eur. J. Biochem. 271, 1814–1819 (2004).

    CAS  PubMed  Google Scholar 

  104. Caterina, M. J. et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824 (1997).

    CAS  PubMed  Google Scholar 

  105. Caterina, M. J. & Julius, D. The vanilloid receptor: a molecular gateway to the pain pathway. Annu. Rev. Neurosci. 24, 487–517 (2001).

    CAS  PubMed  Google Scholar 

  106. Koplas, P. A., Rosenberg, R. L. & Oxford, G. S. The role of calcium in the desensitization of capsaicin responses in rat dorsal root ganglion neurons. J. Neurosci. 17, 3525–3537 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Southall, M. D. et al. Activation of epidermal vanilloid receptor-1 induces release of proinflammatory mediators in human keratinocytes. J. Pharmacol. Exp. Ther. 304, 217–222 (2003). Presents a new concept of the role of keratinocytes in inflammation and nociception.

    CAS  PubMed  Google Scholar 

  108. Bodo, E. et al. A hot new twist to hair biology: involvement of vanilloid receptor-1 (VR1/TRPV1) signaling in human hair growth control. Am. J. Pathol. 166, 985–998 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Meier, T. et al. Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study. Pain 106, 151–158 (2003).

    CAS  PubMed  Google Scholar 

  110. Steinhoff, M. et al. Neurophysiological, neuroimmunological and neuroendocrine basis of pruritus. J. Invest. Dermatol. (in the press).

  111. Peier, A. M. et al. A TRP channel that senses cold stimuli and menthol. Cell 108, 705–715 (2002).

    CAS  PubMed  Google Scholar 

  112. Story, G. M. et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112, 819–829 (2003).

    CAS  PubMed  Google Scholar 

  113. Wei, E. T. & Seid, D. A. AG-3–5: a chemical producing sensations of cold. J. Pharm. Pharmacol. 35, 110–112 (1983).

    CAS  PubMed  Google Scholar 

  114. Patapoutian, A., Peier, A. M., Story, G. M. & Viswanath, V. ThermoTRP channels and beyond: mechanisms of temperature sensation. Nature Rev. Neurosci. 4, 529–539 (2003).

    CAS  Google Scholar 

  115. Kobayashi, K. et al. Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with αδ/c-fibers and colocalization with trk receptors. J. Comp. Neurol. 493, 596–606 (2005).

    CAS  PubMed  Google Scholar 

  116. Reid, G. ThermoTRP channels and cold sensing: what are they really up to? Pflugers Arch. 451, 250–263 (2005).

    CAS  PubMed  Google Scholar 

  117. Lee, H. & Caterina, M. J. TRPV channels as thermosensory receptors in epithelial cells. Pflugers Arch. 451, 160–167 (2005).

    CAS  PubMed  Google Scholar 

  118. Green, B. G. Sensory characteristics of camphor. J. Invest. Dermatol. 94, 662–666 (1990).

    CAS  PubMed  Google Scholar 

  119. Peier, A. M. et al. A heat-sensitive TRP channel expressed in keratinocytes. Science 296, 2046–2049 (2002).

    CAS  PubMed  Google Scholar 

  120. Xu, H., Blair, N. T. & Clapham, D. E. Camphor activates and strongly desensitizes the transient receptor potential vanilloid subtype 1 channel in a vanilloid-independent mechanism. J. Neurosci. 25, 8924–8937 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Chung, M. K., Lee, H., Mizuno, A., Suzuki, M. & Caterina, M. J. TRPV3 and TRPV4 mediate warmth-evoked currents in primary mouse keratinocytes. J. Biol. Chem. 279, 21569–21575 (2004).

    CAS  PubMed  Google Scholar 

  122. Moqrich, A. et al. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science 307, 1468–1472 (2005). Evidence for a role of keratinocytes in the transduction process.

    CAS  PubMed  Google Scholar 

  123. Stein, C., Schafer, M. & Machelska, H. Attacking pain at its source: new perspectives on opioids. Nature Med. 9, 1003–1008 (2003).

    CAS  PubMed  Google Scholar 

  124. Steinhoff, M. et al. Modern aspects of cutaneous neurogenic inflammation. Arch. Dermatol. 139, 1479–1488 (2003).

    PubMed  Google Scholar 

  125. Stander, S. et al. Neurophysiology of pruritus: cutaneous elicitation of itch. Arch Dermatol. 139, 1463–1470 (2003).

    PubMed  Google Scholar 

  126. Minami, M., Maekawa, K., Yabuuchi, K. & Satoh, M. Double in situ hybridization study on coexistence of μ-, δ- and κ-opioid receptor mRNAs with preprotachykinin A mRNA in the rat dorsal root ganglia. Brain Res. Mol. Brain Res. 30, 203–210 (1995).

    CAS  PubMed  Google Scholar 

  127. Satoh, M. & Minami, M. Molecular pharmacology of the opioid receptors. Pharmacol. Ther. 68, 343–364 (1995).

    CAS  PubMed  Google Scholar 

  128. Devane, W. A., Dysarz, F. A., Johnson, M. R., Melvin, L. S. & Howlett, A. C. Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol. 34, 605–613 (1988).

    CAS  PubMed  Google Scholar 

  129. Matsuda, L. A., Lolait, S. J., Brownstein, M. J., Young, A. C. & Bonner, T. I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561–564 (1990).

    CAS  PubMed  Google Scholar 

  130. Munro, S., Thomas, K. L. & Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61–65 (1993).

    CAS  PubMed  Google Scholar 

  131. Pertwee, R. G. Evidence for the presence of CB1 cannabinoid receptors on peripheral neurones and for the existence of neuronal non-CB1 cannabinoid receptors. Life Sci. 65, 597–605 (1999).

    CAS  PubMed  Google Scholar 

  132. Coutts, A. A., Irving, A. J., Mackie, K., Pertwee, R. G. & Anavi-Goffer, S. Localisation of cannabinoid CB(1) receptor immunoreactivity in the guinea pig and rat myenteric plexus. J. Comp. Neurol. 448, 410–422 (2002).

    CAS  PubMed  Google Scholar 

  133. Ahluwalia, J., Urban, L., Bevan, S., Capogna, M. & Nagy, I. Cannabinoid 1 receptors are expressed by nerve growth factor- and glial cell-derived neurotrophic factor-responsive primary sensory neurones. Neuroscience. 110, 747–753 (2002).

    CAS  PubMed  Google Scholar 

  134. Stander, S., Schmelz, M., Metze, D., Luger, T. & Rukwied, R. Distribution of cannabinoid receptor 1 (CB1) and 2 (CB2) on sensory nerve fibers and adnexal structures in human skin. J. Dermatol. Sci. 38, 177–188 (2005).

    PubMed  Google Scholar 

  135. Galiegue, S. et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur. J. Biochem. 232, 54–61 (1995).

    CAS  PubMed  Google Scholar 

  136. Facci, L. et al. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc. Natl Acad. Sci. USA 92, 3376–3380 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Zhang, J. et al. Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur. J. Neurosci. 17, 2750–2754 (2003).

    PubMed  Google Scholar 

  138. Re, G., Barbero, R., Miolo, A. & Di, M. V. Palmitoylethanolamide, endocannabinoids and related cannabimimetic compounds in protection against tissue inflammation and pain: potential use in companion animals. Vet. J. 29 Nov 2005 (doi:10.1016/j.pain.2005.10.003).

  139. Di, M., V, Bifulco, M. & De Petrocellis, L. The endocannabinoid system and its therapeutic exploitation. Nature Rev. Drug Discov. 3, 771–784 (2004).

    Google Scholar 

  140. MacCarrone, M. et al. The endocannabinoid system in human keratinocytes. Evidence that anandamide inhibits epidermal differentiation through CB1 receptor-dependent inhibition of protein kinase C, activation protein-1, and transglutaminase. J. Biol. Chem. 278, 33896–33903 (2003).

    CAS  PubMed  Google Scholar 

  141. Oddi, S. et al. Confocal microscopy and biochemical analysis reveal spatial and functional separation between anandamide uptake and hydrolysis in human keratinocytes. Cell. Mol. Life Sci. 62, 386–395 (2005).

    CAS  PubMed  Google Scholar 

  142. Johanek, L. M. & Simone, D. A. Activation of peripheral cannabinoid receptors attenuates cutaneous hyperalgesia produced by a heat injury. Pain 109, 432–442 (2004).

    CAS  PubMed  Google Scholar 

  143. Diaz-Laviada, I. & Ruiz-Llorente, L. Signal transduction activated by cannabinoid receptors. Mini Rev. Med. Chem. 5, 619–630 (2005).

    CAS  PubMed  Google Scholar 

  144. Rukwied, R., Watkinson, A., McGlone, F. & Dvorak, M. Cannabinoid agonists attenuate capsaicin-induced responses in human skin. Pain 102, 283–288 (2003).

    CAS  PubMed  Google Scholar 

  145. Dvorak, M., Watkinson, A., McGlone, F. & Rukwied, R. Histamine induced responses are attenuated by a cannabinoid receptor agonist in human skin. Inflamm. Res 52, 238–245 (2003).

    CAS  PubMed  Google Scholar 

  146. Begg, M. et al. Evidence for novel cannabinoid receptors. Pharmacol. Ther. 106, 133–145 (2005).

    CAS  PubMed  Google Scholar 

  147. Fattore, L. et al. Cannabinoids and reward: interactions with the opioid system. Crit. Rev. Neurobiol. 16, 147–158 (2004).

    CAS  PubMed  Google Scholar 

  148. Vigano, D., Rubino, T. & Parolaro, D. Molecular and cellular basis of cannabinoid and opioid interactions. Pharmacol. Biochem. Behav. 81, 360–368 (2005).

    CAS  PubMed  Google Scholar 

  149. Vigano, D. et al. Molecular mechanisms involved in the asymmetric interaction between cannabinoid and opioid systems. Psychopharmacology (Berl). 182, 527–536 (2005).

    CAS  PubMed  Google Scholar 

  150. Ibrahim, M. M. et al. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc. Natl Acad. Sci. USA. 102, 3093–3098 (2005). Analgesic effects of CB 2 agonists were shown here to be based on peripheral release of endogenous opioids; therefore, this indirect effect has to be discussed.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Koltzenburg, M., Handwerker, H. O. & Torebjörk, H. E. The ability of humans to localise noxious stimuli. Neurosci. Lett. 150, 219–222 (1993).

    CAS  PubMed  Google Scholar 

  152. Schmidt, R. et al. Novel classes of responsive and unresponsive C nociceptors in human skin. J. Neurosci. 15, 333–341 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Weidner, C. et al. Functional attributes discriminating mechano-insensitive and mechano-responsive C nociceptors in human skin. J. Neurosci. 19, 10184–10190 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Klede, M., Handwerker, H. O. & Schmelz, M. Central origin of secondary mechanical hyperalgesia. J. Neurophysiol. 90, 353–359 (2003).

    PubMed  Google Scholar 

  155. Schmelz, M. et al. Active 'itch fibers' in chronic pruritus. Neurology 61, 564–566 (2003).

    CAS  PubMed  Google Scholar 

  156. Schmelz, M. et al. Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J. Neurophysiol. 89, 2441–2448 (2003). Prostaglandin induced activation is found only in histamine-sensitive pruriceptors — this is evidence for itch-specific neurons.

    CAS  PubMed  Google Scholar 

  157. Wahlgren, C. F. & Ekblom, A. Two-point discrimination of itch in patients with atopic dermatitis and healthy subjects. Acta Derm. Venereol. (Stockh.) 76, 48–51 (1996).

    CAS  Google Scholar 

  158. Ikoma, A., Handwerker, H., Miyachi, Y. & Schmelz, M. Electrically evoked itch in humans. Pain 113, 148–154 (2005).

    PubMed  Google Scholar 

  159. Shelley, W. B. & Arthur, R. P. Mucunain, the active pruritogenic proteinase of cowhage. Science 122, 469–470 (1955).

    CAS  PubMed  Google Scholar 

  160. Hägermark, O. Influence of antihistamines, sedatives, and aspirin on experimental itch. Acta Derm. Venereol. 53, 363–368 (1973).

    PubMed  Google Scholar 

  161. Tuckett, R. P. & Wei, J. Y. Response to an itch-producing substance in cat. II. Cutaneous receptor populations with unmyelinated axons. Brain Res. 413, 95–103 (1987).

    CAS  PubMed  Google Scholar 

  162. Wei, J. Y. & Tuckett, R. P. Response of cat ventrolateral spinal axons to an itch-producing stimulus (cowhage). Somatosens. Mot. Res. 8, 227–239 (1991).

    CAS  PubMed  Google Scholar 

  163. Darsow, U. et al. New aspects of itch pathophysiology: component analysis of atopic itch using the 'Eppendorf Itch Questionnaire'. Int. Arch. Allergy Immunol. 124, 326–331 (2001).

    CAS  PubMed  Google Scholar 

  164. Yosipovitch, G. et al. Itch characteristics in Chinese patients with atopic dermatitis using a new questionnaire for the assessment of pruritus. Int. J. Dermatol. 41, 212–216 (2002).

    PubMed  Google Scholar 

  165. Melzack, R. The McGill Pain Questionnaire: major properties and scoring methods. Pain 1, 277–299 (1975).

    CAS  PubMed  Google Scholar 

  166. Green, B. G. & Shaffer, G. S. The sensory response to capsaicin during repeated topical exposures: differential effects on sensations of itching and pungency. Pain 53, 323–334 (1993).

    CAS  PubMed  Google Scholar 

  167. Simone, D. A. et al. Comparison of responses of primate spinothalamic tract neurons to pruritic and algogenic stimuli. J. Neurophysiol. 91, 213–222 (2004).

    PubMed  Google Scholar 

  168. Schmelz, M. A neural pathway for itch. Nature Neurosci. 4, 9–10 (2001).

    CAS  PubMed  Google Scholar 

  169. Craig, A. D. How do you feel? Interoception: the sense of the physiological condition of the body. Nature Rev. Neurosci. 3, 655–666 (2002).

    CAS  Google Scholar 

  170. Treede, R. D., Kenshalo, D. R., Gracely, R. H. & Jones, A. The cortical representation of pain. Pain 79, 105–111 (1999).

    CAS  PubMed  Google Scholar 

  171. Vogt, B. A. Pain and emotion interactions in subregions of the cingulate gyrus. Nature Rev. Neurosci. 6, 533–544 (2005).

    CAS  Google Scholar 

  172. Bushnell, M. C. & Apkarian, A. V. in Wall and Melzack's Textbook of Pain (eds McMahon, S. B. & Koltzenburg, M.) 107–124 (Churchill Livingstone, Edinburgh, 2005).

    Google Scholar 

  173. Apkarian, A. V., Bushnell, M. C., Treede, R. D. & Zubieta, J. K. Human brain mechanisms of pain perception and regulation in health and disease. Eur. J. Pain. 9, 463–484 (2005).

    PubMed  Google Scholar 

  174. Brooks, J. C., Zambreanu, L., Godinez, A., Craig, A. D. & Tracey, I. Somatotopic organisation of the human insula to painful heat studied with high resolution functional imaging. Neuroimage. 27, 201–209 (2005).

    CAS  PubMed  Google Scholar 

  175. Craig, A. D. A new view of pain as a homeostatic emotion. Trends Neurosci. 26, 303–307 (2003). Basic consideration of the role of pain (and itch) with major implications for central imaging.

    CAS  PubMed  Google Scholar 

  176. Kwan, C. L., Crawley, A. P., Mikulis, D. J. & Davis, K. D. An fMRI study of the anterior cingulate cortex and surrounding medial wall activations evoked by noxious cutaneous heat and cold stimuli. Pain. 85, 359–374 (2000).

    CAS  PubMed  Google Scholar 

  177. Moulton, E. A., Keaser, M. L., Gullapalli, R. P. & Greenspan, J. D. Regional intensive and temporal patterns of functional MRI activation distinguishing noxious and innocuous contact heat. J. Neurophysiol. 93, 2183–2193 (2005).

    CAS  PubMed  Google Scholar 

  178. Brooks, J. & Tracey, I. From nociception to pain perception: imaging the spinal and supraspinal pathways. J. Anat. 207, 19–33 (2005).

    PubMed  PubMed Central  Google Scholar 

  179. Hsieh, J. C. et al. Urge to scratch represented in the human cerebral cortex during itch. J. Neurophysiol. 72, 3004–3008 (1994). Pioneering work on central imaging of pruritus.

    CAS  PubMed  Google Scholar 

  180. Drzezga, A. et al. Central activation by histamine-induced itch: analogies to pain processing: a correlational analysis of O-15 H2O positron emission tomography studies. Pain 92, 295–305 (2001).

    CAS  PubMed  Google Scholar 

  181. Darsow, U. et al. Processing of histamine-induced itch in the human cerebral cortex: a correlation analysis with dermal reactions. J. Invest. Dermatol. 115, 1029–1033 (2000).

    CAS  PubMed  Google Scholar 

  182. Mochizuki, H. et al. Imaging of central itch modulation in the human brain using positron emission tomography. Pain 105, 339–346 (2003).

    PubMed  Google Scholar 

  183. McGlone, F., Rukwied, R., Howard, M. & Hitchcock, D. in Itch — Basic Mechanisms and Therapy (eds. Yosipovitch, G., Greaves, M. W., Fleischer, A. B. & McGlone, F.) 51–62 (Marcel Dekker Inc, New York, Basel, 2004).

    Google Scholar 

  184. Walter, B. et al. Brain activation by histamine prick test-induced itch. J. Invest. Dermatol. 125, 380–382 (2005).

    CAS  PubMed  Google Scholar 

  185. Ikoma, A. et al. Differential activation in the secondary somatosensory cortex by electrically evoked itch and pain: a human functional MRI study. Soc. Neurosci. Abstr. 53. 11 (2005).

    Google Scholar 

  186. Schmelz, M. & Handwerker, H. O. in Textbook of Pain (eds. McMahon, S. B. & Koltzenburg, M.) 219–227 (Elsevier, Philadelphia, 2006).

    Google Scholar 

  187. Ayres, S. J. The fine art of scratching. JAMA 189, 1003–1007 (1964).

    PubMed  Google Scholar 

  188. Kepecs, J. G. & Robin, M. Studies on itching. Psychosom. Med. 17, 87–95 (1955).

    CAS  PubMed  Google Scholar 

  189. Bishop, G. H. Skin as organ of senses with special reference to itching sensation. J. Invest. Dermatol. 11, 143–154 (1948).

    CAS  PubMed  Google Scholar 

  190. Aoki, T. 'Pleasure of scratch' is a complex sensation of itch and pain. 2nd International Workshop for the Study of Itch, 23–25 Oct (2003).

    Google Scholar 

  191. Laihinen, A. Assessment of psychiatric and psychosocial factors disposing to chronic outcome of dermatoses. Acta Derm. Venereol. Suppl (Stockh). 156, 46–48 (1991).

    CAS  PubMed  Google Scholar 

  192. Kringelbach, M. L. The human orbitofrontal cortex: linking reward to hedonic experience. Nature Rev. Neurosci. 6, 691–702 (2005).

    CAS  Google Scholar 

  193. Zubieta, J. K. et al. Regional μ opioid receptor regulation of sensory and affective dimensions of pain. Science 293, 311–315 (2001).

    CAS  PubMed  Google Scholar 

  194. Niemeier, V., Kupfer, J. & Gieler, U. Observations during an itch inducing lecture. Dermatol. Psychosom. 1, 15–18 (2000).

    Google Scholar 

  195. Evans, P. R. Referred itch (Mitempfindungen). Br. Med. J. 2, 839–841 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Nakayama, K. Observing conspecifics scratching induces a contagion of scratching in Japanese monkeys (Macaca fuscata). J. Comp. Psychol. 118, 20–24 (2004).

    PubMed  Google Scholar 

  197. Rizzolatti, G. & Craighero, L. The mirror-neuron system. Annu. Rev. Neurosci. 27, 169–192 (2004).

    CAS  PubMed  Google Scholar 

  198. Iacoboni, M. Neural mechanisms of imitation. Curr. Opin. Neurobiol. 15, 632–637 (2005).

    CAS  PubMed  Google Scholar 

  199. Schurmann, M. et al. Yearning to yawn: the neural basis of contagious yawning. Neuroimage. 24, 1260–1264 (2005).

    PubMed  Google Scholar 

  200. Schmelz, M., Schmidt, R., Handwerker, H. O. & Torebjörk, H. E. Encoding of burning pain from capsaicin-treated human skin in two categories of unmyelinated nerve fibres. Brain 123, 560–571 (2000).

    PubMed  Google Scholar 

  201. Dyck, P. J. et al. Intradermal recombinant human nerve growth factor induces pressure allodynia and lowered heat pain threshold in humans. Neurology 48, 501–505 (1997).

    CAS  PubMed  Google Scholar 

  202. Iversen, L. Cannabis and the brain. Brain 126, 1252–1270 (2003).

    PubMed  Google Scholar 

  203. Katugampola, R., Church, M. K. & Clough, G. F. The neurogenic vasodilator response to endothelin-1: a study in human skin in vivo. Exp. Physiol. 85, 839–846 (2000).

    CAS  PubMed  Google Scholar 

  204. Nicol, G. D. ET — phone the pain clinic. Trends Neurosci. 27, 177–180 (2004).

    CAS  PubMed  Google Scholar 

  205. 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 

  206. 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. 286, 1140–1145 (1998).

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Dermatology, Kyoto University, Shogin-Kawahara-cho 54, Sakyo-ku, 606-8507, Kyoto, Japan

    Akihiko Ikoma

  2. Department of Dermatology, IZKF Münster, and Boltzmann Institute for Immunobiology of the Skin,

    Martin Steinhoff

  3. Department of Dermatology, University Hospital, Von-Esmarch-Str. 58, Münster, 48149, Germany

    Sonja Ständer

  4. Departments of Dermatology, Neurobiology and Anatomy, Wake Forest University School of Medicine, Winston-Salem, 27157, North Carolina, USA

    Gil Yosipovitch

  5. Department of Anaesthesiology, Mannheim, University of Heidelberg, Theodor Kutzer Ufer 1–3, Manheim, 68135, Germany

    Martin Schmelz

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Glossary

Central sensitization

Plastic changes in the CNS (adaptive or pathological) that lead to enhanced responses and/or lower thresholds.

Allodynia

The perception of a stimulus as painful when previously the same stimulus was reported to be non-painful.

Punctate hyperalgesia

Type of central sensitization for pain in which the pain elicited by punctate mechanical stimuli is more prolonged and stronger than normally experienced.

Alloknesis

Type of central sensitization for itch in which touch triggers the sensation of itch.

Punctate hyperknesis

Type of central sensitization for itch in which the itch evoked by punctate mechanical stimuli is more prolonged and stronger than normally experienced.

Iontophoresis

A non-invasive method of propelling high concentrations of a charged substance, normally medication or bioactive-agents, transdermally by repulsive electromotive force using a small electrical charge applied to an iontophoretic chamber containing a similarly charged active agent and its vehicle.

Positron emission tomography

(PET). In vivo imaging technique used for diagnostic examination that involves the acquisition of physiological images based on the detection of positrons, which are emitted from a radioactive substance previously administered to the patient.

Functional MRI

(fMRI). Technique that allows the spatial investigation of central neuronal activation by the measurement of the secondary increase of perfusion following neuronal activity.

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Ikoma, A., Steinhoff, M., Ständer, S. et al. The neurobiology of itch. Nat Rev Neurosci 7, 535–547 (2006). https://doi.org/10.1038/nrn1950

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