Abstract
Pruritus or itch generated in the skin is one of the most widespread symptoms associated with various dermatological and systemic (immunological) conditions. Although many details about the molecular mechanisms of the development of both acute and chronic itch were uncovered in the last 2 decades, our understanding is still incomplete and the clinical management of pruritic conditions is one of the biggest challenges in daily dermatological practice. Recent research revealed molecular interactions between pruriceptive sensory neurons and surrounding cutaneous cell types including keratinocytes, as well as resident and transient cells of innate and adaptive immunity. Especially in inflammatory conditions, these cutaneous cells can produce various mediators, which can contribute to the excitation of pruriceptive sensory fibers resulting in itch sensation. There also exists significant communication in the opposite direction: sensory neurons can release mediators that maintain an inflamed, pruritic tissue-environment. In this review, we summarize the current knowledge about the sensory transduction of pruritus detailing the local intercellular interactions that generate itch. We especially emphasize the role of various pruritic mediators in the bidirectional crosstalk between cutaneous non-neuronal cells and sensory fibers. We also list various dermatoses and immunological conditions associated with itch, and discuss the potential immune-neuronal interactions promoting the development of pruritus in the particular diseases. These data may unveil putative new targets for antipruritic pharmacological interventions.
Highlights
Specialty section: This article was submitted to Inflammation Pharmacology, a section of the journal Frontiers in Pharmacology
gastrin releasing peptide (GRP) was detected in peripheral sensory neurons (Sun and Chen, 2007; Barry et al, 2016, 2020) and its expression was found to be elevated in chronic itch conditions in mice (Zhao et al, 2013) and primates (Nattkemper et al, 2013)
In certain cases, transient receptor potential ankyrin 1 (TRPA1) and TRPV1 can play a synergistic role in the same process. They were recently shown as key transducers of heat-pain together with transient receptor potential melastatin 3 (TRPM3), another thermosensitive nociceptor TRP channel significantly coexpressed with TRPV1 and TRPA1
Summary
Itch is a common somatosensory modality well-known from the everyday life. It was defined as an “unpleasant sensation that elicits the desire or reflex to scratch” by Samuel Hafenreffer in the 17th century (Ikoma et al, 2006, p. 535), which is a pragmatic and valid definition even today. Pruriceptive itch is peripherally induced itch generated in the skin In this case, itch is evoked by locally released pruritogens exciting the pruriceptive nerve endings in the skin. Itch is evoked by locally released pruritogens exciting the pruriceptive nerve endings in the skin The release of these chemical mediators can be triggered acutely by external irritants (e.g. insect bite, poisonous plants or skin sensitizers) or may be related to various, typically inflammatory skin conditions which can affect an extended area of the skin, and is likely to be chronic. Neurogenic itch is evoked by the (peripheral) excitation of itch sensitive neurons, but in this case the triggering pruritic mediators stem from a “central source” and their production is related to systemic diseases, such as kidney failure, hepatic conditions or immunological diseases. We focus on the role of peripheral interactions in the generation of pruritus, mainly discussing cases of pruriceptive and some neurogenic pruritus as these are evoked by the excitation of pruriceptive cutaneous nerve endings
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