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The Journal of Neuroscience, July 16, 2003, 23(15):6176-6180

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Proteinase-Activated Receptor-2 Mediates Itch: A Novel Pathway for Pruritus in Human Skin

Martin Steinhoff,^4 * Ulrich Neisius,^1,2 * Akihiko Ikoma,¹ Manigé Fartasch,² Gisela Heyer,² Per S. Skov,³ Thomas A. Luger,⁴ and Martin Schmelz^1,5

Departments of ¹Physiology and Experimental Pathophysiology, and ²Dermatology, University of Erlangen, 91054 Erlangen, Germany, ³The Reference Laboratory, University of Copenhagen, 2100 Copenhagen, Denmark, ⁴Department of Dermatology, University of Münster, 48149 Münster, Germany, and ⁵Department of Anesthesiology and Intensive Care Medicine, University of Heidelberg, 68135 Mannheim, Germany

We examined whether neuronal proteinase-activated receptor-2 (PAR-2) may be involved in pruritus of human skin. The endogenous PAR-2 agonist tryptase was increased up to fourfold in atopic dermatitis (AD) patients. PAR-2 was markedly enhanced on primary afferent nerve fibers in skin biopsies of AD patients. Intracutaneous injection of endogenous PAR-2 agonists provoked enhanced and prolonged itch when applied intralesionally. Moreover, itch upon mast cell degranulation was abolished by local antihistamines in controls but prevailed in AD patients. Thus, we identified enhanced PAR-2 signaling as a new link between inflammatory and sensory phenomena in AD patients. PAR-2 therefore represents a promising therapeutic target for the treatment of cutaneous neurogenic inflammation and pruritus.

Key words: protease-activated receptors; neuroimmunology; neurophysiology; sensory nerve; atopy; tryptase

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Received Nov. 13, 2002; revised Apr. 18, 2003; accepted May. 2, 2003.

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