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Although the medical definition of itch has been in existence for 360 years, only in the last 20 years have we begun to understand the basic mechanisms that underlie this unique sensation. Therapeutics that specifically target chronic itch as a pathologic entity are currently still not available. Recent seminal advances in itch circuitry within the nervous system have intersected with discoveries in immunology in unexpected ways to rapidly inform emerging treatment strategies. The current review aims to introduce these basic concepts in itch biology and highlight how distinct immunologic pathways integrate with recently identified itch-sensory circuits in the nervous system to inform a major new paradigm of neuroimmunology and therapeutic development for chronic itch.
Learn More >Atopic dermatitis (AD) is associated with itch, pain, and sleep disturbance, all of which may contribute toward cognitive dysfunction.
Learn More >Atopic dermatitis is a prevalent inflammatory skin condition characterized by itch and dry skin, which affects 15-20% of children and 3-5% of adults. This article reviews epidemiological, clinical and experimental data to provide an overview of the most important disease mechanisms in atopic dermatitis. Genetic predisposition, environmental insults, atopic triggers, complex host immune response and skin barrier changes, and altered skin microbiota are discussed. Whilst our understanding of atopic dermatitis has improved dramatically in recent years, many basic aspects are still not understood. Further research is needed to fully understand this complex skin disease.
Learn More >Single cell sequencing has provided unprecedented information about the transcriptomic diversity of somatosensory systems. Here we describe a simple and versatile in situ hybridization (ISH) based approach for mapping this information back to the tissue. We illustrate the power of this approach by demonstrating that ISH localization with just eight probes is sufficient to distinguish all major classes of neurons in sections of the trigeminal ganglion. To further simplify the approach and make transcriptomic class assignment and cell segmentation automatic we developed a machine learning approach for analyzing images from multiprobe ISH experiments. We demonstrate the power of in situ class assignment by examining the expression patterns of voltage gated sodium channels that play roles in distinct somatosensory processes and pain. Specifically, this analysis resolves intrinsic problems with single cell sequencing related to the sparseness of data leading to ambiguity about gene expression patterns. We also used the multiplex in situ approach to study the projection fields of the different neuronal classes. Our results demonstrate that the surface of the eye and meninges are targeted by broad arrays of neural classes despite their very different sensory properties but exhibit idiotypic patterns of innervation at a quantitative level. Very surprisingly, itch related neurons extensively innervated the meninges, indicating that these transcriptomic cell classes are not simply labeled lines for triggering itch. Together, these results substantiate the importance of a sensory neuron's peripheral and central connections as well as its transcriptomic class in determining its role in sensation.
Learn More >There is an unmet medical need for pruritus associated with chronic kidney disease, a distressing complication characterized by generalized and persistent itch affecting 20% to 40% of patients undergoing hemodialysis. Here we report the results of a phase 2 trial evaluating the efficacy and safety of a novel peripherally restricted kappa opioid receptor agonist, difelikefalin, in adult patients undergoing hemodialysis with pruritus.
Learn More >Medical marijuana is becoming widely available to patients in the U.S. and with recreational marijuana now legalized in many states, patient interest is on the rise. The endocannabinoid system plays an important role in skin homeostasis in addition to broader effects on neurogenic responses such as pruritus and nociception, inflammation, and immune reactions. There are numerous studies of in vitro and animal models that provide insight into the possible mechanisms of cannabinoid modulation on pruritus, with the most evidence behind neuronal modulation of both peripheral itch fibers and centrally-acting cannabinoid receptors. In addition, human studies, while limited due to differences in cannabinoids used, disease models, and delivery method, have consistently shown significant reductions in both scratching and symptomatology in chronic pruritus. Clinical studies that have shown reduction in pruritus in several dermatologic (atopic dermatitis, psoriasis, asteatotic eczema, prurigo nodularis, allergic contact dermatitis) and systemic (uremic pruritus, cholestatic pruritus) diseases. These preliminary human studies warrant controlled trials to confirm the benefit of cannabinoids for treatment of pruritus and to standardize treatment regimens and indications. In patients who have refractory chronic pruritus after standard therapies, cannabinoid formulations may be considered as an adjuvant therapy where it is legal.
Learn More >Previous research mainly uses skin-manipulating methods to induce itch. In comparison to these methods, itch induced by audiovisual stimuli lacks a direct skin manipulation.
Learn More >Current patient-reported outcome measures for itch are limited and may not capture its full impact on health-related quality of life (HRQOL). We sought to develop, calibrate and validate banks of questions assessing the HRQOL impact of itch as part of Patient-Reported Outcomes Measurement Information System® (PROMIS®). A systematic process of literature review, content-expert review, qualitative research, testing in a sample of 600 adults, classical test theory methods, and item response theory (IRT) analyses were applied. Exploratory and confirmatory factor analyses were followed by item response theory (IRT) model and item fit analyses. Four itch-related item banks were developed: (1) general concerns, (2) mood and sleep, (3) clothing and physical activity, and (4) scratching behavior. IRT and expert content review narrowed the item banks to 25, 18, 15 and 5 items, respectively. Validity of the item banks was supported by good convergent and discriminant validity with itch intensity, internal consistency and no significant floor or ceiling effects. In conclusion, the PROMIS Itch Questionnaire (PIQ) banks have excellent measurement properties and efficiently and comprehensively assess the burden of itch.
Learn More >Atopic dermatitis (AD) is a chronic and recurrent inflammatory skin disease, affecting up to 10% to 20% of children and 3% of adults. Although allergen sensitization, skin barrier abnormalities and type 2 immune responses are involved, the exact molecular pathogenesis of AD remains unclear. MicroRNAs (miRNAs) are short (19-25 nucleotides) single-stranded RNA molecules that regulate gene expression at post-transcriptional level and are implicated in the pathogenesis of many inflammatory and immunological skin disorders. This systematic review sought to summarize our current understanding regarding the role of miRNAs in AD development. We searched articles indexed in PubMed (MEDLINE) and Web of Science databases using Medical Subject Heading (MeSH) or Title/Abstract words ('microRNA/miRNA' and 'atopic dermatitis/eczema') from inception through January 2020. Observational studies revealed dysregulation of miRNAs, including miR-143, miR-146a, miR-151a, miR-155 and miR-223, in AD patients. Experimental studies confirmed their functions in regulating keratinocyte proliferation/apoptosis, cytokine signalling and nuclear factor-κB-dependent inflammatory responses, together with T helper 17 and regulatory T cell activities. Altogether, this systematic review brings together contemporary findings on how deregulation of miRNAs contributes to AD.
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