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Pain is a frequent symptom of atopic dermatitis (AD).
Learn More >Cutaneous somatosensory modalities play pivotal roles in generating a wide range of sensorimotor behaviors, including protective and corrective reflexes that dynamically adapt ongoing movement and posture. How interneurons (INs) in the dorsal horn encode these modalities and transform them into stimulus-appropriate motor behaviors is not known. Here, we use an intersectional genetic approach to functionally assess the contribution that eight classes of dorsal excitatory INs make to sensorimotor reflex responses. We demonstrate that the dorsal horn is organized into spatially restricted excitatory modules composed of molecularly heterogeneous cell types. Laminae I/II INs drive chemical itch-induced scratching, laminae II/III INs generate paw withdrawal movements, and laminae III/IV INs modulate dynamic corrective reflexes. These data reveal a key principle in spinal somatosensory processing, namely, sensorimotor reflexes are driven by the differential spatial recruitment of excitatory neurons.
Learn More >The opioid peptides and their receptors have been linked to multiple key biological processes in the nervous system. Here we review the functions of the kappa opioid receptor (KOR) and its endogenous agonists dynorphins (Goldstein A, Tachibana S, Lowney LI, Hunkapiller M, Hood L, Proc Natl Acad Sci U S A 76:6666-6670, 1979) in modulating itch and pain (nociception). Specifically, we discuss their roles relative to recent findings that tell us more about the cells and circuits which are impacted by this opioid and its receptor and present reanalysis of single-cell sequencing data showing the expression profiles of these molecules. Since the KOR is relatively specifically activated by peptides derived from the prodynorphin gene and other opioid peptides that show lower affinities, this will be the only interactions we consider (Chavkin C, Goldstein A, Nature 291:591-593, 1981; Chavkin C, James IF, Goldstein A, Science 215:413-415, 1982), although it was noted that at higher doses peptides other than dynorphins might stimulate KOR (Lai J, Luo MC, Chen Q, Ma S, Gardell LR, Ossipov MH, Porreca F, Nat Neurosci 9:1534-1540, 2006). This review has been organized based on anatomy with each section describing the effect of the kappa opioid system in a specific location but let us not forget that most of these circuits are interconnected and are therefore interdependent.
Learn More >In recent years, studying the central mechanism of itch has gained momentum. However, a proper meta-analysis has not been conducted in this domain. In this study, we tried to respond to this need. A systematic search and a meta-analysis were carried out to estimate the central mechanism of itch. The itch matrix comprises the thalamus and the parietal, secondary somatosensory, insular and cingulate cortices. We have shown that the basal ganglia (BG) play an important role in itch reduction. Finally, we explored itch processing in AD patients and observed that the itch matrix in these patients was different. In conclusion, this is the first meta-analysis on the central mechanisms of itch perception and processing. Our study demonstrated that different modalities of itch induction can produce a common pattern of activity in the brain and provided further insights into understanding the underlying nature of itch central perception.
Learn More >Atopic dermatitis is a common, chronic inflammatory skin disease that is characterized by skin barrier dysfunction, inflammation and intense itch. Although the exact mechanisms behind its pathogenesis remain unclear, it is evident that the complex interplay among barrier dysfunction, inflammation and itch are critical in its development, progression and chronicity. Abnormalities in filaggrin, intercellular lipids and tight junctions induce barrier-disrupted skin, which produces thymic stromal lymphopoietin, interleukin (IL)-25 and IL-33; these in turn promote skin inflammation characterized by type 2 immune deviation. This inflammation then downregulates the expression of filaggrin in keratinocytes and exacerbates epidermal barrier dysfunction. Furthermore, various itch mediators/pruritogens produced during this inflammatory process can act directly on sensory nerves and cause itch. In this review, we summarize the basics and recent advances in our understanding of the pathophysiology of atopic dermatitis focusing on three aspects: barrier dysfunction, skin inflammation and itch.
Learn More >Itch is defined as an unpleasant sensation that provokes a desire to scratch. Our understanding of neuronal circuits for itch information transmission and processing in the spinal dorsal horn (SDH) has progressively advanced following the identification of SDH neuron subsets that are crucial for scratching behavior in models of itch. However, little is known about the control of acute and chronic itch by descending signals from the brain to the SDH. In this study, using genetic approaches that enable cell-type and circuit-specific functional manipulation, we reveal an intrinsic potential of locus coeruleus (LC)-noradrenergic (NAergic) neurons that project to the SDH to control acute and chronic itch. Activation and silencing of SDH-projecting LC-NAergic neurons reduced and enhanced scratching behavior, respectively, in models of histamine-dependent and -independent acute itch. Furthermore, in a model of chronic itch associated with contact dermatitis, repetitive scratching behavior was suppressed by the activation of the descending LC-NAergic pathway and by knocking out NA transporters specific to descending LC-NAergic neurons using a CRISPR-Cas9 system. Moreover, patch-clamp recording using spinal slices showed that noradrenaline facilitated inhibitory synaptic inputs onto gastrin-releasing peptide receptor-expressing SDH neurons, a neuronal subset known to be essential for itch transmission. Our findings suggest that descending LC-NAergic signaling intrinsically controls acute and chronic itch and provide potential therapeutic strategies for the treatment of acute and chronic itch.
Learn More >Prurigo nodularis (PN) is a chronic, pruritic, debilitating disease. Previous studies found that chronic pruritus in general negatively affects patients' quality of life (QoL). However, results about the impact of PN on QoL are conflicting. Our objective was to assess the QoL burden of PN. A systematic review was conducted of all published studies that assessed QoL measures in PN. OVID MEDLINE, EMBASE, SCOPUS, and Web of Science were searched. Pooled meta-analysis (means) was performed using random-effects weighting. Overall, 13 studies met inclusion criteria. All studies identified QoL reductions in patients suffering from PN compared to control groups. The most common QoL instrument used was the Dermatology Life Quality Index [n = 9 studies; pooled mean (95% confidence interval): 13.8 (10.6-16.9), denoting a very large effect]. In particular, PN was associated with substantial impact on multiple domains of QoL. No publication bias was detected. In conclusion, QoL is negatively impacted in PN. Future studies are necessary to determine the best instruments of measuring QoL in PN patients, better understand this association, and assess the impact in males and females separately. PROSPERO CRD42019136193.
Learn More >Flare reactions arise due to the release of vasodilators from sensory nerves caused by antidromic transmission of action potentials after the induction of itch.
Learn More >Dendritic cells (DCs) of the cDC2 lineage initiate allergic immunity and in the dermis are marked by their expression of CD301b. CD301b dermal DCs respond to allergens encountered in vivo, but not in vitro. This suggests that another cell in the dermis may sense allergens and relay that information to activate and induce the migration of CD301b DCs to the draining lymph node (dLN). Using a model of cutaneous allergen exposure, we show that allergens directly activated TRPV1 sensory neurons leading to itch and pain behaviors. Allergen-activated sensory neurons released the neuropeptide Substance P, which stimulated proximally located CD301b DCs through the Mas-related G-protein coupled receptor member A1 (MRGPRA1). Substance P induced CD301b DC migration to the dLN where they initiated T helper-2 cell differentiation. Thus, sensory neurons act as primary sensors of allergens, linking exposure to activation of allergic-skewing DCs and the initiation of an allergic immune response.
Learn More >Individuals with autism spectrum disorders (ASDs) imitate observed behavior less than age-matched and typically developing peers, resulting in deterred learning ability and social interaction. However, this deficit lacks preclinical assessment tools. A previous study has shown that mice exhibit contagious itch behavior while viewing a scratching demonstrator mouse, as opposed to an ambulating demonstrator mouse, but whether autism mouse models imitate observed scratching behavior remains unknown. Here, we investigated contagious itch behavior in the mouse model of fragile X syndrome (FXS), a common form of inherited intellectual disabilities with a high risk for ASDs. We found that the mouse model of FXS shows deficits in contagious itch behavior. Our findings can be used as a new preclinical assessment tool for measuring imitative deficits in the study of neurodevelopmental disorders including FXS.
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