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Available from: Steven G Shimada, Mar 28, 2014
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    ABSTRACT: Persistent itch is a common symptom of allergic contact dermatitis (ACD) and represents a significant health burden. The chemokine CXCL10 is predominantly produced by epithelial cells during ACD. Although the chemokine CXCL10 and its receptor CXCR3 are implicated in the pathophysiology of ACD, it is largely unexplored for the itch and pain accompanying this disorder. Here, we showed that CXCL10 and CXCR3 mRNA, protein and signaling activity were upregulated in the dorsal root ganglion (DRG) after contact hypersensitivity (CHS), a murine model of ACD, induced by squaric acid dibutylester. CXCL10 directly activated a subset of cutaneous DRG neurons innervating the area of CHS through neuronal CXCR3. In behavioral tests, a CXCR3 antagonist attenuated spontaneous itch- but not pain-like behaviors directed to the site of CHS. Injection of CXCL10 into the site of CHS elicited site-directed itch- but not pain-like behaviors, but neither type of CXCL10-evoked behaviors was observed in control mice. These results suggest that CXCL10/CXCR3 signaling mediates allergic itch but not inflammatory pain in the context of skin inflammation. Thus, the upregulation of CXCL10/CXCR3 signaling in sensory neurons may contribute to itch associated with ACD. Targeting the CXCL10/CXCR3 signaling might be beneficial for the treatment of allergic itch.
    Pain 04/2015; DOI:10.1097/j.pain.0000000000000208 · 5.84 Impact Factor
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    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.
    Clinical Reviews in Allergy & Immunology 05/2015; DOI:10.1007/s12016-015-8488-5 · 4.73 Impact Factor
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    ABSTRACT: There have been many exciting recent advances in our understanding of the molecular and cellular basis of itch. These discoveries cover diverse aspects of itch sensation, from the identification of new receptors to the characterization of spinal cord itch circuits. A common thread of these studies is that they demonstrate that itch sensory signals are segregated from input for other somatosensory modalities, such as pain, touch, and thermosensation. This specificity is achieved by the expression of dedicated receptors and transmitters in a select population of sensory neurons which detect pruritogens. Further, recent studies show that itch specificity is maintained in a spinal cord circuit by the utilization of specific neurotransmitters and cognate receptors to convey input along a distinct cellular pathway. Copyright © 2015. Published by Elsevier Ltd.
    Current Opinion in Neurobiology 02/2015; 34C:61-66. DOI:10.1016/j.conb.2015.01.017 · 6.77 Impact Factor