The neurobiology of itch

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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.

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.

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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.

References

  1. 1

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

  2. 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.

  3. 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).

  4. 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.

  5. 5

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

  6. 6

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

  7. 7

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

  8. 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).

  9. 9

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

  10. 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).

  11. 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).

  12. 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. 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).

  14. 14

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

  15. 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).

  16. 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).

  17. 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).

  18. 18

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

  19. 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).

  20. 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).

  21. 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).

  22. 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).

  23. 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).

  24. 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).

  25. 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).

  26. 26

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

  27. 27

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

  28. 28

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

  29. 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).

  30. 30

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

  31. 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).

  32. 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).

  33. 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).

  34. 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.

  35. 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).

  36. 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).

  37. 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).

  38. 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).

  39. 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. 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.

  41. 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).

  42. 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).

  43. 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).

  44. 44

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

  45. 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).

  46. 46

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

  47. 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).

  48. 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).

  49. 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).

  50. 50

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

  51. 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. 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).

  53. 53

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

  54. 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.

  55. 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).

  56. 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).

  57. 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).

  58. 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).

  59. 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.

  60. 60

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

  61. 61

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

  62. 62

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

  63. 63

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

  64. 64

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

  65. 65

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

  66. 66

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

  67. 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).

  68. 68

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

  69. 69

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

  70. 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).

  71. 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).

  72. 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).

  73. 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).

  74. 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).

  75. 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.

  76. 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).

  77. 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).

  78. 78

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

  79. 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).

  80. 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.

  81. 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).

  82. 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).

  83. 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).

  84. 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).

  85. 85

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

  86. 86

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

  87. 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).

  88. 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).

  89. 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).

  90. 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.

  91. 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).

  92. 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).

  93. 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).

  94. 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).

  95. 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).

  96. 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).

  97. 97

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

  98. 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).

  99. 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).

  100. 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).

  101. 101

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

  102. 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).

  103. 103

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

  104. 104

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

  105. 105

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

  106. 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).

  107. 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.

  108. 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).

  109. 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).

  110. 110

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

  111. 111

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

  112. 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).

  113. 113

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

  114. 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).

  115. 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).

  116. 116

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

  117. 117

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

  118. 118

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

  119. 119

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

  120. 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).

  121. 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).

  122. 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.

  123. 123

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

  124. 124

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

  125. 125

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

  126. 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).

  127. 127

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

  128. 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).

  129. 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).

  130. 130

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

  131. 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).

  132. 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).

  133. 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).

  134. 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).

  135. 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).

  136. 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).

  137. 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).

  138. 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. 139

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

  140. 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).

  141. 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).

  142. 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).

  143. 143

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

  144. 144

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

  145. 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).

  146. 146

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

  147. 147

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

  148. 148

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

  149. 149

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

  150. 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.

  151. 151

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

  152. 152

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

  153. 153

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

  154. 154

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

  155. 155

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

  156. 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.

  157. 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).

  158. 158

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

  159. 159

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

  160. 160

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

  161. 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).

  162. 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).

  163. 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).

  164. 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).

  165. 165

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

  166. 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).

  167. 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).

  168. 168

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

  169. 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).

  170. 170

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

  171. 171

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

  172. 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).

  173. 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).

  174. 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).

  175. 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.

  176. 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).

  177. 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).

  178. 178

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

  179. 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.

  180. 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).

  181. 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).

  182. 182

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

  183. 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).

  184. 184

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

  185. 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).

  186. 186

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

  187. 187

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

  188. 188

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

  189. 189

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

  190. 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).

  191. 191

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

  192. 192

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

  193. 193

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

  194. 194

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

  195. 195

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

  196. 196

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

  197. 197

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

  198. 198

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

  199. 199

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

  200. 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).

  201. 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).

  202. 202

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

  203. 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).

  204. 204

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

  205. 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).

  206. 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).

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Correspondence to 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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