DOI QR코드

DOI QR Code

가려움증의 신경전달 경로

The Neurotransmitter Pathway of Itching

  • 조정원 (경상대학교 의과대학 피부과학교실) ;
  • 김지연 (경상대학교 의과대학 피부과학교실)
  • Jo, Jeong Won (Department of Dermatology, College of Medicine, Gyeongsang National University) ;
  • Kim, Chi-Yeon (Department of Dermatology, College of Medicine, Gyeongsang National University)
  • 투고 : 2017.05.18
  • 심사 : 2017.05.29
  • 발행 : 2017.05.30

초록

가려움증의 분류는 수용체성 가려움증(Pruritoceptive itch), 신경병증 가려움증(Neuropathic itch), 신경성 가려움증(Neurogenic itch), 심인성 가려움증(Psychogenic itch)의 신경생리학적 기전에 따른 4가지 카테고리로 분류하는 것이 일반적이었으나 최근 임상적인 기준을 통해 분류하기도 한다. 가려움증의 신경전달 경로는 히스타민-의존 경로와 히스타민-비의존 경로 2가지로 나뉘며 각 가려움증 매개체마다 서로 다른 수용체와 신경펩티드가 작용한다. 히스타민, BAM8-22, chloroquine 등의 가려움증 매개체는 히스타민-의존 경로를 통해 신호가 전달되며 cowhage spicule, 단백분해효소(protease), TSLP (Thymic stromal lymphopoietin) 등의 매개체가 히스타민-비의존 경로와 관련있다는 보고가 있다. 이러한 가려움증 매개체, 수용체, 신경펩티드는 가려움증 치료의 대상이 된다. 가려움증과 통증은 대표적인 유해자극으로서 과거에는 두 감각이 하나의 유해자극수용체를 통해 전달된다는 주장이 있었지만 최근 밝혀진 바에 따르면 가려움증과 통증은 독립적인 신경전달체계를 가지고 있으며 두 신경체계는 서로 억제작용을 한다. 가려움증 뉴런의 선택적 소집단이 존재한다는 주장을 뒷받침하는 연구들이 이 주장에 무게를 싣고 있다. 또한 가려움증과 통증의 상호 길항작용에 대해서도 다양한 기전으로 설명되고 있다. 최근에도 새롭게 연구되는 매개체와 수용체들이 많은 연구들을 통해 밝혀지고 있다. 특히 최근에는 히스타민 4 수용체에 대한 연구가 활발히 진행되고 있는데, 이는 T 세포 같은 면역세포 자체에 발현되어 있어 이 H4 수용체를 차단하는 치료제는 말초의 매개체를 차단하는 기존의 히스타민 수용체 차단제와는 달리 가려움증 만성화에 중요한 염증 반응 자체를 억제할 수 있다는 점에서 그 유용성이 크다고 할 수 있다. 가려움증의 기본적인 발생 기전에 대한 이해와 새로운 가려움증 매개체에 대한 연구는 효과적인 치료법의 개발로 이어질 것이며 이것이 가려움증 연구가 나아갈 바로 생각한다.

It was common that the classification of itching was classified into four categories according to the neurophysiological mechanisms of pruritoceptive itching, neuropathic itching, neurogenic itching and psychogenic itching. Recently it was classified by clinical criteria. The neurotransmission pathway of itch is divided into histamine-dependent pathway and histamine-independent pathway. Different receptors and neuropeptides act on each itch mediator. Itch mediators such as histamine, BAM8-22, and chloroquine are transmitted through the histamine-dependent pathway. Cowhage spicule, protease, and TSLP (Thymic stromal lymphopoietin) have been reported to be related to the histamine-independent pathway. These itch mediators, receptors, and neuropeptides are the targets of treatment for itching. Although itching and pain are typical noxious stimuli, and in the past, it was argued that two senses were transmitted through one noxious stimulus receptor. It has recently been shown that itching and pain have an independent neurotransmitter system and both neuronal systems inhibit each other. In addition, the mutual antagonism between itching and pain is explained by various mechanisms. Recently, many new mediators and receptors are being studied. The studies on histamine 4 receptor (H4 receptor) have been actively conducted. And the H4 receptors are expressed in immune cells such as T cells. The therapeutic agent for blocking the H4 receptor can inhibit the inflammatory reaction itself, which is important for the itching and chronicization. Understanding the underlying mechanisms of itching and studying new itch mediators will lead to the development of effective therapies, and this is what I think the itching study will go on.

키워드

참고문헌

  1. Akiyama, T., Tominaga, M., Takamori, K., Carstens, M. I. and Carstens, E. 2014. Roles of glutamate, substance P and gastrin-releasing peptide as spinal neurotransmitters of histaminergic and nonhistaminergic itch. Pain 155, 80-92. https://doi.org/10.1016/j.pain.2013.09.011
  2. Alvarez, F. J., Cervantes, C., Blasco, I., Villalba, R., Martinez- Murillo, R., Polak, J. M. and Rodrigo, J. 1988. Presence of calcitonin gene-related peptide (CGRP) and substance P (SP) immunoreactivity in intraepidermal free nerve endings of cat skin. Brain Res. 442, 391-395. https://doi.org/10.1016/0006-8993(88)91532-6
  3. Andrea, S. R. and Ruf, W. 2012. Protease-activated receptor 2 signaling in inflammation. Semin. Immunopathol. 34, 133-149. https://doi.org/10.1007/s00281-011-0289-1
  4. Andrew, D. and Craig, A. D. 2001. Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch. Nat. Neurosci. 4, 72-77. https://doi.org/10.1038/82924
  5. Barry, G. D., Le, G. T. and Fairlie, D. P. 2006. Agonists and antagonists of protease activated receptors (PARs). Curr. Med. Chem. 13, 243-265. https://doi.org/10.2174/092986706775476070
  6. Bergasa, N. V., Alling, D. W., Talbot, T. L., Swain, M. G., Yurdaydin, C., Turner, M. L., Schmitt, J. M., Walker, E. C. and Jones, E. A. 1995. Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial. Ann. Intern. Med. 123, 161-167. https://doi.org/10.7326/0003-4819-123-3-199508010-00001
  7. Bernhard, J. D. 2005. Itch and pruritus: what are they, and how should itches be classified? Dermatol. Ther. 18, 288-291. https://doi.org/10.1111/j.1529-8019.2005.00040.x
  8. Brain, S. D., Tippins, J. R., Morris, H. R., MacIntyre, I. and Williams, T. J. 1986. Potent vasodilator activity of calcitonin gene-related peptide in human skin. J. Invest. Dermatol. 87, 533-536. https://doi.org/10.1111/1523-1747.ep12455620
  9. Cowden, J., Zhang, M., Dunford, P. J. and Thurmond, R. L. 2010. The histamine H4 receptor mediates inflammation and pruritus in Th2-dependent dermal inflammation. J. Invest. Dermatol. 130, 1023-1033. https://doi.org/10.1038/jid.2009.358
  10. Darsow, U., Drzezga, A., Frisch, M., Munz, F., Weilke, F., Bartenstein, P., Schwaiger, M. and Ring, J. 2000. Processing of histamine-induced itch in the human cerebral cortex: a correlation analysis with dermal reactions. J. Invest. Dermatol. 115, 1029-1033. https://doi.org/10.1046/j.1523-1747.2000.00193.x
  11. Davidson, S. and Giesler, G. J. 2010. The multiple pathways for itch and their interactions with pain. Trends. Neurosci. 33, 550-558. https://doi.org/10.1016/j.tins.2010.09.002
  12. Davidson, S., Zhang, X., Khasabov, S. G., Moser, H. R., Honda, C. N., Simone, D. A. and Giesler, G. J. Jr. 2012. Pruriceptive spinothalamic tract neurons: physiological properties and projection targets in the primate. J. Neurophysiol. 108, 1711-1723. https://doi.org/10.1152/jn.00206.2012
  13. Davidson, S., Zhang, X., Khasabov, S. G., Simone, D. A. and Giesler, G. J. Jr. 2009. Relief of itch by scratching: state-dependent inhibition of primate spinothalamic tract neurons. Nat. Neurosci. 12, 544-546. https://doi.org/10.1038/nn.2292
  14. Davidson, S., Zhang, X., Yoon, C. H., Khasabov, S. G., Simone, D. A. and Giesler, G. J. Jr. 2007. The itch-producing agents histamine and cowhage activate separate populations of primate spinothalamic tract neurons. J. Neurosci. 27, 10007-10014. https://doi.org/10.1523/JNEUROSCI.2862-07.2007
  15. Diana, M. B., Wilson, S. R. and Hoon, M. A. 2014. Why we scratch an itch: the molecules, cells and circuits of itch. Nat. Neurosci. 17, 175-182. https://doi.org/10.1038/nn.3619
  16. Duval, A. and Dubertret, L. 2009. Aprepitant as an antipruritic agent? N. Engl. J. Med. 361, 1415-1416. https://doi.org/10.1056/NEJMc0906670
  17. Gutzmer, R., Mommert, S., Gschwandtner, M., Zwingmann, K., Stark, H. and Werfel, T. 2009. The histamine H4 receptor is functionally expressed on T(H)2 cells. J. Allergy Clin. Immunol. 123, 619-625. https://doi.org/10.1016/j.jaci.2008.12.1110
  18. Han, L., Ma, C., Liu, Q., Weng, H. J., Cui, Y., Tang, Z., Kim, Y., Nie, H., Qu, L., Patel, K. N., Li, Z., McNeil, B., He, S., Guan, Y., Xiao, B., Lamotte, R. H. and Dong, X. 2013. A subpopulation of nociceptors specifically linked to itch. Nat. Neurosci. 16, 174-182. https://doi.org/10.1038/nn.3289
  19. Ikoma, A., Cevikbas, F., Kempkes, C. and Steinhoff, M. 2011. Anatomy and neurophysiology of pruritus. Semin. Cutan. Med. Surg. 30, 64-70. https://doi.org/10.1016/j.sder.2011.04.001
  20. Johanek, L. M., Meyer, R. A., Friedman, R. M., Greenquist, K. W., Shim, B., Borzan, J., Hartke, T., LaMotte, R. H. and Ringkamp, M. 2008. A role for polymodal C-fiber afferents in nonhistaminergic itch. J. Neurosci. 28, 7659-7669. https://doi.org/10.1523/JNEUROSCI.1760-08.2008
  21. Kato, T., Takai, T., Fujimura, T., Matsuoka, H., Ogawa, T., Murayama, K., Ishii, A., Ikeda, S., Okumura, K. and Ogawa, H. 2009. Mite serine protease activates protease-activated receptor-2 and induces cytokine release in human keratinocytes. Allergy 64, 1366-1374. https://doi.org/10.1111/j.1398-9995.2009.02023.x
  22. Kumagai, H., Ebata, T., Takamori, K., Muramatsu, T., Nakamoto, H. and Suzuki, H. 2010. Effect of a novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 337 haemodialysis patients: a Phase III, randomized, double-blind, placebo-controlled study. Nephrol. Dial. Transplant. 25, 1251-1257. https://doi.org/10.1093/ndt/gfp588
  23. Lee, H., Naughton, N. N., Woods, J. H. and Ko, M. C. 2007. Effects of butorphanol on morphine-induced itch and analgesia in primates. Anesthesiology 107, 478-485. https://doi.org/10.1097/01.anes.0000278876.20263.a7
  24. Liu, B., Escalera, J., Balakrishna, S., Fan, L., Caceres, A. I., Robinson, E., Sui, A., McKay, M. C., McAlexander, M. A., Herrick, C. A. and Jordt, S. E. 2013. TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis. FASEB. J. 27, 3549-3535 https://doi.org/10.1096/fj.13-229948
  25. Liu, Q., Sikand, P., Ma, C., Tang, Z., Han, L., Li, Z., Sun, S., LaMotte, R. H. and Dong, X. 2012. Mechanisms of itch evoked by b-alanine. J. Neurosci. 32, 14532-14537. https://doi.org/10.1523/JNEUROSCI.3509-12.2012
  26. Liu, Q., Tang, Z., Surdenikova, L., Kim, S., Patel, K. N., Kim, A., Ru, F., Guan, Y., Weng, H. J., Geng, Y., Undem, B. J., Kollarik, M., Chen, Z. F., Anderson, D. J. and Dong, X. 2009. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 139, 1353-1365. https://doi.org/10.1016/j.cell.2009.11.034
  27. McNeil, B. and Dong, X. 2012. Peripheral mechanisms of itch. Neurosci. Bull. 28, 100-110. https://doi.org/10.1007/s12264-012-1202-1
  28. Chuquilin, M., Alghalith, Y. and Fernandez, K. H. 2016. Neurocutaneous disease, cutaneous neuroanatomy and mechanisms of itch and pain. J. Am. Acad. Dermatol. 74, 197-212. https://doi.org/10.1016/j.jaad.2015.04.060
  29. Mishra, S. K. and Hoon, M. A. 2013. The cells and circuitry for itch responses in mice. Science 340, 968-971. https://doi.org/10.1126/science.1233765
  30. Mochizuki, H., Tashiro, M., Kano, M., Sakurada, Y., Itoh, M. and Yanai, K. 2003. Imaging of central itch modulation in the human brain using positron emission tomography. Pain 105, 339-346. https://doi.org/10.1016/S0304-3959(03)00249-5
  31. Namer, B., Carr, R., Johanek, L. M., Schmelz, M., Handwerker, H. O., Ringkamp, M. 2008. Separate peripheral pathways for pruritus in man. J. Neurophysiol. 100, 2062-2069. https://doi.org/10.1152/jn.90482.2008
  32. Natalie, M. M., Glass, J. S. and Carroll, B. T. 2015. Acute pain management in dermatology, mechanisms and pathways. J. Am. Acad. Dermatol. 73, 533-540. https://doi.org/10.1016/j.jaad.2015.03.061
  33. Page, K., Strunk, V. S. and Hershenson, M. B. 2003. Cockroach proteases increase IL-8 expression in human bronchial epithelial cells via activation of protease-activated receptor (PAR)-2 and extracellular-signal-regulated kinase. J. Allergy Clin. Immunol. 112, 1112-1118. https://doi.org/10.1016/j.jaci.2003.08.050
  34. Papoiu, A. D., Coghill, R. C., Kraft, R. A., Wang, H. and Yosipovitch, G. 2012. A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch. Neuroimage 59, 3611-3623. https://doi.org/10.1016/j.neuroimage.2011.10.099
  35. Patel, K. N. and Dong, X. 2010. An itch to be scratched. Neuron 68, 334-339. https://doi.org/10.1016/j.neuron.2010.10.018
  36. Peer, G., Kivity, S., Agami, O., Fireman, E., Silverberg, D., Blum, M. and laina, A. 1996. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet 348, 1552-1554. https://doi.org/10.1016/S0140-6736(96)04176-1
  37. R, Morrison, A. R. and Pentland, A. P. 1996. Histamine in human epidermal cells is induced by ultraviolet light injury. J. Invest. Dermatol. 106, 785-789. https://doi.org/10.1111/1523-1747.ep12346356
  38. Reddy, V. B., Iuga, A. O., Shimada, S. G., LaMotte, R. H. and Lerner, E. A. 2008. Cowhage-evoked itch is mediated by a novel cysteine protease: a ligand of protease-activated receptors. J. Neurosci. 28, 4331-4335. https://doi.org/10.1523/JNEUROSCI.0716-08.2008
  39. Reddy, V. B., Shimada, S. G., Sikand, P., Lamotte, R. H. and Lerner, E. A. 2010. Cathepsin S elicits itch and signals via protease-activated receptors. J. Invest. Dermatol. 130, 1468-1470. https://doi.org/10.1038/jid.2009.430
  40. Roberson, D. P., Gudes, S., Sprague, J. M., Patoski, H. A., Robson, V. K., Blasl, F., Duan, B., Oh, S. B., Bean, B. P., Ma, Q., Binshtok, A. M. and Woolf, C. J. 2013. Activity-dependent silencing reveals functionally distinct itch-generating sensory neurons. Nat. Neurosci. 16, 910-918. https://doi.org/10.1038/nn.3404
  41. Ross, S. E. 2011. Pain and itch: insights into the neural circuits of aversive somatosensation in health and disease. Curr. Opin. Neurobiol. 21, 880-887. https://doi.org/10.1016/j.conb.2011.10.012
  42. Saiah, M., Borgeat, A., Wilder-Smith, O. H., Rifat, K. and Suter, P. M. 1994. Epidural-morphine-induced pruritus: propofol versus naloxone. Anesth. Analg. 78, 1110-1113.
  43. Schmelz, M. 2001. A neural pathway for itch. Nat. Neurosci. 4, 9-10. https://doi.org/10.1038/82956
  44. Schmelz, M., Hilliges, M., Schmidt, R., Orstavik, K., Vahlquist, C., Weidner, C., Handwerker, H. O. and Torebjork, H. E. 2003. Active ''itch fibers'' in chronic pruritus. Neurology 61, 564-566. https://doi.org/10.1212/01.WNL.0000078193.64949.08
  45. Schmelz, M., Schmidt, R., Bickel, A., Handwerker, H. O. and Torebjork, H. E. 1997. Specific C-receptors for itch in human skin. J. Neurosci. 17, 8003-8008. https://doi.org/10.1523/JNEUROSCI.17-20-08003.1997
  46. Shim, W. S., Tak, M. H., Lee, M. H., Kim, M., Kim, M., Koo, J. Y., Lee, C. H., Kim, M. and Oh, U. 2007. TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J. Neurosci. 27, 2331- 2337. https://doi.org/10.1523/JNEUROSCI.4643-06.2007
  47. Stander, S., Raap, U., Weisshaar, E., Schmelz, M., Mettang, T., Handwerker, H. and Luger, T. A. 2011. Pathogenesis of pruritus. J. Dtsch. Dermatol. Ges. 9, 456-463.
  48. Staender, S. and Schmelz, M. 2006. Chronic itch and pain? similarities and differences. Eur. J. Pain 10, 473-478. https://doi.org/10.1016/j.ejpain.2006.03.005
  49. Stander, S., Siepmann, D., Herrgott, I., Sunderkotter, C. and Luger, T. A. 2015. Targeting the neurokinin receptor 1 with aprepitant: a novel antipruritic strategy. PLoS One 5, e10968.
  50. Stefansson, K., Brattsand, M., Roosterman, D., Kempkes, C., Bocheva, G., Steinhoff, M. and Egelrud, T. 2008. Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. J. Invest. Dermatol. 128, 18-25. https://doi.org/10.1038/sj.jid.5700965
  51. Steinhoff, M., Corvera, C. U., Thoma, M. S., Kong, W., McAlpine, B. E., Caughey, G. H., Ansel, J. C. and Bunnett, N. W. 1999. Proteinase-activated receptor-2 in human skin: tissue distribution and activation of keratinocytes by mast cell tryptase. Exp. Dermatol. 8, 282-294.
  52. Sukhtankar, D. D. and Ko, M. C. 2013. Physiological function of gastrin-releasing peptide and neuromedin B receptors in regulating itch scratching behavior in the spinal cord of mice. PLoS One 8, e67422 https://doi.org/10.1371/journal.pone.0067422
  53. Sun, Y. G. and Chen, Z. F. 2007. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 448, 700-703. https://doi.org/10.1038/nature06029
  54. Sun, Y. G., Zhao, Z. Q., Meng, X. L., Yin, J., Liu, X. Y. and Chen, Z. F. 2009. Cellular basis of itch sensation. Science 325, 1531-1534. https://doi.org/10.1126/science.1174868
  55. Susan, T. D. 1986. A review of pruritus. J. Am. Acad. Dermatol. 14, 375-392. https://doi.org/10.1016/S0190-9622(86)70047-9
  56. Tippins, J. R. 1986. CGRP: a novel neuropeptide from the calcitonin gene is the most potent vasodilator known. J. Hypertens. Suppl. 4, S102-S105.
  57. Togashi, Y., Umeuchi, H., Okano, K., Ando, N., Yoshizawa, Y., Honda, T., Kawamura, K., Endoh, T., Utsumi, J., Kamei, J., Tanaka, T. and Nagase, H. 2002. Antipruritic activity of the kappa-opioid receptor agonist, TRK-820. Eur. J. Pharmacol. 435, 259-264. https://doi.org/10.1016/S0014-2999(01)01588-6
  58. Wilson, S. R., Nelson, A. M., Batia, L., Morita, T., Estandian, D., Owens, D. M., Lumpkin, E. A. and Bautista, D. M. 2013. The ion channel TRPA1 is required for chronic itch. J. Neurosci. 33, 9283-9294. https://doi.org/10.1523/JNEUROSCI.5318-12.2013
  59. Wilson, S. R., The, L., Batia, L. M., Beattie, K., Katibah, G. E., McClain, S. P., Pellegrino, M., Estandian, D. M. and Bautista, D. M. 2013. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell 155, 285-295. https://doi.org/10.1016/j.cell.2013.08.057
  60. Won, C. H. and Hong, S. P. 2010. Pathophysiology and therapy of pruritus in allergic and atopic diseases. Kor. J. Asthma Allergy Clin. Immunol. 30, 184-192.
  61. Yosipovitch, G., Carstens, E. and McGlone, F. 2007. Chronic itch and chronic pain: analogous mechanisms. Pain 131, 4-7. https://doi.org/10.1016/j.pain.2007.04.017
  62. Yosipovitch, G., Greaves, M. W. and Schmelz, M. 2003. Itch. Lancet 361, 690-694. https://doi.org/10.1016/S0140-6736(03)12570-6