Itch, the hallmark of atopic dermatitis, has a significant impact on quality of life for patients with this disease. Various central and peripheral mediators have been suggested to play a role in the pathophysiology of atopic eczema itch. Significant cross-talk occurs among stratum corneum, keratinocytes, immune cells, and nerve fibers, which are in close proximity to one another and induce itch. The impaired barrier function associated with the itch-scratch cycle further augments this vicious cycle. Recent advances in our understanding of itch pathophysiology shed light on peripheral and central neural sensitization of nerve fibers that contribute significantly to itch in atopic dermatitis. Recently, several new mediators have been described as associated with itch in atopic dermatitis, including serine proteases, interleukin 31, and nerve growth factor. This review covers the peripheral and central mechanisms and mediators involved in pathogenesis of itch in atopic dermatitis.
"Many other mediators are also produced by and secreted from skin-constituent cells in close contact to sensory nerves (Steinhoff et al., 2006). They can activate and sensitize pruritic nerve endings and even modulate their growth, as do nerve growth factors and chemorepellents (Yamaguchi et al., 2008; Yosipovitch and Papoiu, 2008). As for the receptor system, it is notable that KCs, mast cells, and fibroblasts express neurokinin-1 receptor (Ohkubo and Nakanishi, 1991; Scholzen et al., 1998), which is the receptor for SP. "
[Show abstract][Hide abstract] ABSTRACT: Cholecystokinin (CCK) serves as a gastrointestinal hormone and also functions as a neuropeptide in the central nervous system (CNS). CCK may be a downregulator in the CNS, as represented by its anti-opioid properties. The existence of CCK in the peripheral nervous system has also been reported. We investigated the suppressive effects of various CCKs on peripheral pruritus in mice. The clipped backs of ICR mice were painted with CCK synthetic peptides and injected intradermally with substance P (SP). The frequency of SP-induced scratching was reduced significantly by topical application of sulfated CCK8 (CCK8S) and CCK7 (CCK7S), but not by nonsulfated CCK8, CCK7, or CCK6. Dermal injection of CCK8S also suppressed the scratching frequency, suggesting that dermal cells as well as epidermal keratinocytes (KCs) are the targets of CCKs. As determined using real-time PCR, mRNA for CCK2R, one of the two types of CCK receptors, was expressed highly in mouse fetal skin-derived mast cells (FSMCs) and moderately in ICR mouse KCs. CCK8S decreased in vitro compound 48/80-promoted degranulation of FSMCs with a transient elevation of the intracellular calcium concentration. These findings suggest that CCK may exert an antipruritic effect via mast cells and that topical CCK may be clinically useful for pruritic skin disorders.
"Identification of the pruritogens and elucidation of their mechanisms of action are very important goals for controlling the pruritus of AD. Several mediators causing pruritus are described in review papers (Stander and Steinhoff, 2002; Yosipovitch and Papoiu, 2008). "
[Show abstract][Hide abstract] ABSTRACT: Atopic dermatitis is a common skin disease affecting up to 10% of children and approximately 2% of adults. Atopic dermatitis exhibits four major symptoms, including intense itching, dry skin, redness and exudation. The "itch-scratch-itch" cycle is one of the major features in atopic dermatitis. The pathophysiology and neurobiology of pruritus is unclear. Currently there are no single and universally effective pharmacological antipruritic drugs for treatment of atopic dermatitis. Thus, controlling of itch is a very important unmet need in patients suffering from atopic dermatitis. This article will update progress during the past 10 years of research in the field of pruritus of atopic dermatitis, focusing on aspects of pruritogens (including inflammatory lipids, histamine, serotonin, proteinases, proteinase-activating receptors, neurotransmitters, neuropeptides, and opioid peptides), antipruritic therapies, and emerging new targets. Based on recent progress, researchers expect to identify exciting possibilities for improved treatments and to develop new antipruritic drugs acting through novel targets, such as histamine H4 receptor, gastrin-releasing peptide receptor, MrgprA3, thromboxane A2 receptor and the putative SPC receptor.
Biomolecules and Therapeutics 07/2010; 18(3). DOI:10.4062/biomolther.2010.18.3.246 · 1.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pruritus measurement is problematic, because of its subjective nature and poor localization. Ratio scales enhance the usefulness of the visual analogue scale (VAS) by reducing variation; other scales such as the generalized labelled magnitude scale may also be useful. Pruritus neuroanatomy includes peripheral receptors, peripheral and central nerves, ascending and descending spinal pathways, and several brain regions. Pruritus receptors include Merkel discs and free nerve endings, and itch receptors have fast or slow adaptation. In this review, we discuss the pathophysiology of pruritus in atopic dermatitis, psoriasis and scabies. Pruritus treatment is reviewed for topical agents and antihistamines. Future research directions are suggested.
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