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Mediators of Chronic Pruritus in Atopic Dermatitis: Getting the Itch Out?

Abstract

For centuries, itch was categorized as a submodality of pain. Recent research over the last decade has led to the realization that itch is in fact a separate and distinct, albeit closely related, sensation. Chronic itch is a common complaint and has numerous etiologies. Various receptors (TRPA1, TRPV1, PAR2, gastrin-releasing peptide receptor (GRPR), Mas-related G proteins), secreted molecules (histamine, nerve growth factor (NGF), substance P (SP), proteases), and cytokines/chemokines (thymic stromal lymphopoietin (TSLP), IL-2, IL-4, IL-13, and IL-31) are implicated as mediators of chronic pruritus. While much remains unknown regarding the mechanisms of chronic itch, this much is certain: there is no singular cause of itch. Rather, itch is caused by a complex interface between skin, keratinocytes, cutaneous nerve fibers, pruritogenic molecules, and the peripheral and central nervous systems. Atopic dermatitis is one of the most itchy skin dermatoses and affects millions worldwide. The sensation of atopic itch is mediated by the interplay between epidermal barrier dysfunction, upregulated immune cascades, and the activation of structures in the central nervous system. Clinicians are in possession of an arsenal of different treatment options ranging from moisturizers, topical immunomodulators, topical anesthetic ion channel inhibitors, systemic immunomodulators, as well as oral drugs capable of reducing neural hypersensitization. Emerging targeted therapies on the horizon, such as dupilumab, promise to usher in a new era of highly specific and efficacious treatments. Alternative medicine, stress reduction techniques, and patient education are also important treatment modalities. This review will focus on the mediators of chronic pruritus mainly associated with atopic dermatitis (atopic itch), as well as numerous different therapeutic options.

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Notes

  1. While MrgprA3 mediates CQ-induced itch in mice, a separate receptor, MrgprC11, is activated by BAM8-22. This is in direct contrast to that in humans, wherein MrgprX1 activation is responsible for both mechanisms.

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The authors have no financial relationships relevant to this article to disclose.

Conflict of Interest

GY is a member of the scientific advisory board of Cosmoderm, TREVI, Creabilis, Velocity, Celgene, Eli Lilly, and Pfizer. NM and PS have no conflicts of interest relevant to this article to disclose.

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Mollanazar, N.K., Smith, P.K. & Yosipovitch, G. Mediators of Chronic Pruritus in Atopic Dermatitis: Getting the Itch Out?. Clinic Rev Allerg Immunol 51, 263–292 (2016). https://doi.org/10.1007/s12016-015-8488-5

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Keywords

  • Atopic dermatitis
  • Chronic pruritus
  • Barrier disruption
  • Nonhistaminergic itch
  • Neural hypersensitization
  • Neuropeptides
  • Pruritus receptor unit
  • Alternative itch therapies
  • Immunomodulators
  • Patient education