Neurophysiologie des Juckreizes^[*]

Zusammenfassung

Die neuronalen Verarbeitungswege für Juckreiz können in die Histamin-abhängigen und Histamin-unabhängigen unterteilt werden. Allerdings kann auch die Aktivierung von normalerweise schmerzverarbeitenden Neuronen Juckreiz auslösen; damit ist eine exakte Trennung von Neuronen in Nozizeptoren und Prurizeptoren nicht mehr einfach möglich. In dieser Übersicht werden die neurophysiologischen Mechanismen des Juckreizes unter physiologischen Bedingungen beschrieben, die jedoch auch bei Patienten mit chronischem Juckreiz bedeutsam sein können. Die Mediatoren für Juckreiz und Schmerz überlappen zu einem großen Teil und auch die Muster der peripheren und zentralen Sensibilisierung sind bei Juckreiz und Schmerz überraschend ähnlich. Es ist daher von großer klinischer Bedeutung, inwiefern die Ähnlichkeiten auch therapeutische Implikationen haben und damit Analgetika auch anti-pruritische Wirkung haben können.

Abstract

Histaminergic and non-histaminergic neuronal pathways for itch have been found in humans. However, even pathways normally involved in pain processing can cause itch. Thus, the differentiation between neuronal pathways for itch and pain has now become disputable. In this review neurophysiological mechanisms that underlie itch sensations under physiological conditions will be discussed that might also be operational in chronic itch conditions. Peripheral mediators of itch and pain overlap to a large extent, and also patterns of peripheral and central sensitisation are similar in chronic pain and chronic itch conditions. It will be of major interest to assess whether the underlying mechanisms for central sensitisation in the itch and pain pathways are also similar, as this might have major therapeutic implications.

^* Erstpublikation in Klin Neurophysiol 2012; 43: 280 – 283

• Literatur

• 1 Schmelz M, Schmidt R, Bickel A et al. Specific C-receptors for itch in human skin. J Neurosci 1997; 17: 8003-8008
• 2 Schmelz M, Schmidt R, Weidner C et al. Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J Neurophysiol 2003; 89: 2441-2448
• 3 Schmidt R, Schmelz M, Weidner C et al. Innervation territories of mechano-insensitive C nociceptors in human skin. J Neurophysiol 2002; 88: 1859-1866
• 4 Wahlgren CF, Ekblom A. Two-point discrimination of itch in patients with atopic dermatitis and healthy subjects. Acta Derm Venereol (Stockh) 1996; 76: 48-51
• 5 Neisius U, Olsson R, Rukwied R et al. Prostaglandin E2 induces vasodilation and pruritus, but no protein extravasation in atopic dermatitis and controls. J Am Acad Dermatol 2002; 47: 28-32
• 6 Schmelz M, Michael K, Weidner C et al. Which nerve fibers mediate the axon reflex flare in human skin?. Neuroreport 2000; 11: 645-648
• 7 Hägermark O. Influence of antihistamines, sedatives, and aspirin on experimental itch. Acta Derm Venereol 1973; 53: 363-368
• 8 Shelley WB, Arthur RP. The neurohistology and neurophysiology of the itch sensation in man. AMA archives of dermatology 1957; 76: 296-323
• 9 Ikoma A, Handwerker H, Miyachi Y et al. Electrically evoked itch in humans. Pain 2005; 113: 148-154
• 10 LaMotte RH, Shimada SG, Green BG et al. Pruritic and nociceptive sensations and dysesthesias from a spicule of cowhage. J Neurophysiol 2009; 101: 1430-1443
• 11 Sikand P, Shimada SG, Green BG et al. Similar itch and nociceptive sensations evoked by punctate cutaneous application of capsaicin, histamine and cowhage. Pain 2009; 144: 66-75
• 12 Tuckett RP, Wei JY. Response to an itch-producing substance in cat. II. Cutaneous receptor population with unmyelinated axons. Brain Research 1987; 413: 95-103
• 13 Johanek LM, Meyer RA, Hartke T et al. Psychophysical and physiological evidence for parallel afferent pathways mediating the sensation of itch. J Neurosci 2007; 27: 7490-7497
• 14 Johanek LM, Meyer RA, Friedman RM et al. A role for polymodal C-fiber afferents in nonhistaminergic itch. J Neurosci 2008; 28: 7659-7669
• 15 Namer B, Carr R, Johanek LM et al. Separate peripheral pathways for pruritus in man. J Neurophysiol 2008; 100: 2062-2069
• 16 Ringkamp M, Schepers RJ, Shimada SG et al. A role for nociceptive, myelinated nerve fibers in itch sensation. J Neurosci 2011; 31: 14841-14849
• 17 Reddy VB, Iuga AO, Shimada SG et al. Cowhage-evoked itch is mediated by a novel cysteine protease: a ligand of protease-activated receptors. J Neurosci 2008; 28: 4331-4335
• 18 Andrew D, Craig AD. Spinothalamic lamina 1 neurons selectively sensitive to histamine: a central neural pathway for itch. Nat Neurosci 2001; 4: 72-77
• 19 Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci 2002; 3: 655-666
• 20 Sun YG, Chen ZF. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 2007; 448: 700-703
• 21 Sun YG, Zhao ZQ, Meng XL et al. Cellular Basis of Itch Sensation. Science 2009; 325: 1531-1534
• 22 Su PY, Ko MC. The role of central gastrin-releasing peptide and neuromedin B receptors in the modulation of scratching behavior in rats. J Pharmacol Exp Ther 2011; 337: 822-829
• 23 Davidson S, Zhang X, Yoon CH et al. The itch-producing agents histamine and cowhage activate separate populations of primate spinothalamic tract neurons. J Neurosci 2007; 27: 10007-10014
• 24 Simone DA, Zhang X, Li J et al. Comparison of responses of primate spinothalamic tract neurons to pruritic and algogenic stimuli. J Neurophysiol 2004; 91: 213-222
• 25 Akiyama T, Carstens MI, Carstens E. Facial injections of pruritogens and algogens excite partly overlapping populations of primary and second-order trigeminal neurons in mice. J Neurophysiol 2010; 104: 2442-2450
• 26 Akiyama T, Merrill AW, Carstens MI et al. Activation of superficial dorsal horn neurons in the mouse by a PAR-2 agonist and 5-HT: potential role in itch. J Neurosci 2009; 29: 6691-6699
• 27 McMahon SB, Koltzenburg M. Itching for an explanation. Trends Neurosci 1992; 15: 497-501
• 28 Handwerker HO. Microneurography of pruritus. Neurosci Lett 2010; 470: 193-196
• 29 Patel KN, Dong X. An itch to be scratched. Neuron 2010; 68: 334-339
• 30 Davidson S, Giesler GJ. The multiple pathways for itch and their interactions with pain. Trends Neurosci 2010; 33: 550-558
• 31 Ma Q. Labeled lines meet and talk: population coding of somatic sensations. J Clin Invest 2010; 120: 3773-3778
• 32 Cevikbas F, Steinhoff M, Ikoma A. Role of spinal neurotransmitter receptors in itch: new insights into therapies and drug development. CNS Neurosci Ther 2010; 17: 742-749
• 33 Ross SE. Pain and itch: insights into the neural circuits of aversive somatosensation in health and disease. Curr Opin Neurobiol 2011;
• 34 Nilsson HJ, Levinsson A, Schouenborg J. Cutaneous field stimulation (CFS): A new powerful method to combat itch. Pain 1997; 71: 49-55
• 35 Brull SJ, Atanassoff PG, Silverman DG et al. Attenuation of experimental pruritus and mechanically evoked dysesthesiae in an area of cutaneous allodynia. Somatosens Mot Res 1999; 16: 299-303
• 36 Simone DA, Nolano M, Johnson T et al. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: Correlation with sensory function. J Neurosci 1998; 18: 8947-8954
• 37 Atanassoff PG, Brull SJ, Zhang J et al. Enhancement of experimental pruritus and mechanically evoked dysesthesiae with local anesthesia. Somatosens Mot Res 1999; 16: 291-298
• 38 Andrew D, Schmelz M, Ballantyne JC. Itch - mechanisms and mediators. 2003; 24: 213-226
• 39 Liu XY, Liu ZC, Sun YG et al. Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell 2011; 147: 447-458
• 40 Kjellberg F, Tramer MR. Pharmacological control of opioid-induced pruritus: a quantitative systematic review of randomized trials. Eur J Anaesthesiol 2001; 18: 346-357
• 41 Kumagai H, Ebata T, Takamori K et al. 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 2010; 25: 1251-1257
• 42 Liu Y, Abdel SO, Zhang L et al. VGLUT2-dependent glutamate release from nociceptors is required to sense pain and suppress itch. Neuron 2010; 68: 543-556
• 43 Lagerstrom MC, Rogoz K, Abrahamsen B et al. VGLUT2-dependent sensory neurons in the TRPV1 population regulate pain and itch. Neuron 2010; 68: 529-542
• 44 Steinhoff M, Neisius U, Ikoma A et al. Proteinase-Activated Receptor-2 Mediates Itch: A Novel Pathway for Pruritus in Human Skin. J Neurosci 2003; 23: 6176-6180
• 45 Steinhoff M, Vergnolle N, Young SH et al. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med 2000; 6: 151-158
• 46 Akiyama T, Carstens MI, Carstens E. Enhanced scratching evoked by PAR-2 agonist and 5-HT but not histamine in a mouse model of chronic dry skin itch. Pain 2010; 151: 378-383
• 47 Grant AD, Cottrell GS, Amadesi S et al. Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice. J Physiol 2007; 578: 715-733
• 48 Dai Y, Wang S, Tominaga M et al. Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain. J Clin Invest 2007; 117: 1979-1987
• 49 Liu Q, Weng HJ, Patel KN et al. The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia. Sci Signal 2011; 4 ra45
• 50 Liu Q, Tang Z, Surdenikova L et al. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 2009; 139: 1353-1365
• 51 Sikand P, Dong X, LaMotte RH. BAM8-22 peptide produces itch and nociceptive sensations in humans independent of histamine release. J Neurosci 2011; 31: 7563-7567
• 52 Liu T, Xu ZZ, Park CK et al. Toll-like receptor 7 mediates pruritus. Nat Neurosci 2010;
• 53 Wilson SR, Gerhold KA, Bifolck-Fisher A et al. TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch. Nat Neurosci 2011; 14: 595-602
• 54 Kremer AE, Martens JJ, Kulik W et al. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology 2010; 139: 1008-1018
• 55 Ma L, Uchida H, Nagai J et al. Evidence for de novo synthesis of lysophosphatidic acid in the spinal cord through phospholipase A2 and autotaxin in nerve injury-induced neuropathic pain. J Pharmacol Exp Ther 2010; 333: 540-546
• 56 Inoue M, Ma L, Aoki J et al. Autotaxin, a synthetic enzyme of lysophosphatidic acid (LPA), mediates the induction of nerve-injured neuropathic pain. Mol Pain 2008; 8: 4-6
• 57 Lane NE, Schnitzer TJ, Birbara CA et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N Engl J Med 2010; 363: 1521-1531
• 58 Tominaga M, Ozawa S, Tengara S et al. Intraepidermal nerve fibers increase in dry skin of acetone-treated mice. J Dermatol Sci 2007; 48: 103-111
• 59 Takano N, Sakurai T, Ohashi Y et al. Effects of high-affinity nerve growth factor receptor inhibitors on symptoms in the NC/Nga mouse atopic dermatitis model. Br J Dermatol 2007; 156: 241-246
• 60 Yamaura K, Doi R, Suwa E et al. A novel animal model of pruritus induced by successive application of glucocorticoid to mouse skin. J Toxicol Sci 2011; 36: 395-401
• 61 Tominaga M, Tengara S, Kamo A et al. Psoralen-ultraviolet A therapy alters epidermal Sema3A and NGF levels and odulates epidermal innervation in atopic dermatitis. J Dermatol Sci 2009; 55: 40-46
• 62 Deising S, Weinkauf B, Blunk J et al. NGF evoked sensitization of muscle fascia nociceptors in humans. Pain 2012; 153: 1673-1679
• 63 Rukwied R, Mayer A, Kluschina O et al. NGF-induces non-inflammatory localized and lasting mechanical and thermal hypersensitivity in human skin. Pain 2010; 148: 407-413
• 64 Weinkauf B, Obreja O, Schmelz M et al. Differential effects of lidocaine on nerve growth factor (NGF)-evoked heat- and mechanical hyperalgesia in humans. Eur J Pain 2012; 16: 543-549
• 65 Rukwied RR, Main M, Weinkauf B et al. NGF sensitizes nociceptors for cowhage- but not histamine-induced itch in human skin. J Invest Dermatol 2012; (im Druck)
• 66 Koltzenburg M. Neural mechanisms of cutaneous nociceptive pain. Clin J Pain 2000; 16: 131-138
• 67 Bickford RGL. Experiments relating to itch sensation, its peripheral mechanism and central pathways. Clin Sci 1938; 3: 377-386
• 68 Simone DA, Alreja M, LaMotte RH. Psychophysical studies of the itch sensation and itchy skin (“alloknesis”) produced by intracutaneous injection of histamine. Somatosens Mot Res 1991; 8: 271-279
• 69 Birklein F, Claus D, Riedl B et al. Effects of cutaneous histamine application in patients with sympathetic reflex dystrophy. Muscle Nerve 1997; 20: 1389-1395
• 70 Baron R, Schwarz K, Kleinert A et al. Histamine-induced itch converts into pain in neuropathic hyperalgesia. Neuroreport 2001; 12: 3475-3478
• 71 Ikoma A, Rukwied R, Stander S et al. Neuronal sensitization for histamine-induced itch in lesional skin of patients with atopic dermatitis. Arch Dermatol 2003; 139: 1455-1458