Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033774 (pruritus)
 14,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathogenesis of acute and chronic (> 6 weeks duration) pruritus is complex and involves in the skin a network of resident cells (e. g., mast cells, keratinocytes, sensory neurons) and transient inflammatory cells (e. g., eosinophils). Though pruritus and pain show overlapping mechanisms, recent studies have provided evidence that pruritus and pain pathogenesis differ in important points. In the skin, the sensory C-nerve fibers have been investigated intensively. Several classes of histamine-sensitive or histamine-insensitve C-fibers have been described. Epidermal and dermal sensory nerve fibres are now assumed to be of major importance in pruritus induction. They interact with keratinocytes, inflammatory cells such as T lymphocytes, eosinophils and basophils which have been shown to release multiple pruritogenic mediators (e.g., nerve growth factor, interleukin-31) which lead to activation, sensitization and sprouting of skin nerves. Specific receptors have been discovered on cutaneous and spinal neurons to be exclusively involved in the processing of pruritic signals. Just recently, the gastrin-releasing peptide receptor (GRPR) was identified on spinal neurons that are crucially involved in pruritus but not pain processing. Chronic pruritus is notoriously difficult to treat. Newer insights into the underlying pathogenesis of pruritus have enabled novel treatment approaches that target the pruritus-specific pathophysiological mechanism. For example, kappa-opioid receptor agonists and neurokinin-1 antagonists have been found to relieve chronic pruritus.
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PMID:Pathogenesis of pruritus. 2120 78

Recent advances in pruritus research have elucidated mediators and neuronal pathways involved in itch transmission, and this fast emerging knowledge may possibly be translated into new therapies in the near future. In the skin and peripheral nerves, potential mediator and receptor therapeutic targets include the H4 histamine receptor, protease-activated receptor 2, serine proteases, cathepsin S, peripheral mu- and kappa-opioid receptors, interleukin-31, transient receptor potential vanilloid 1 and 3, fatty acid amide hydrolase, nerve growth factor and its receptor, acetylcholine, and the Mas-related G protein-coupled receptors. In the spinal cord, gastrin-related peptide and its receptor, as well as substance P and its receptor neurokinin receptor-1 serve as potential therapeutic targets. In the brain, reduction of itch perception and modulation of emotions may possibly be achieved through drugs acting on the anterior cingulate cortex. Clinically, management of pruritus should be instituted early and should address the skin pathology, peripheral neuropathy, central sensitization, and the cognito-affective aspects of the disease.
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PMID:Targeted treatment of pruritus: a look into the future. 2121 93

Cutaneous nerve density is related to abnormal itch perception in dermatoses, such as atopic dermatitis and xerosis. However, the mechanisms underlying the elongation of dermal nerve fibers within the interstitial collagen (CoL) matrix are poorly understood. In this study, a culture system of rat dorsal root ganglion neurons consisting of type I CoL and a Boyden chamber containing a nerve growth factor (NGF) concentration gradient was used. Nerve fibers penetrating into type I CoL gel were observed in the presence of the NGF concentration gradient. Levels of matrix metalloproteinase-8 (MMP-8) mRNA and protein were increased in the cultured neurons and the conditioned medium, respectively. The nerve fiber penetration was dose dependently inhibited by MMP-8 blockers. Moreover, MMP-8 immunoreactivity was partially localized at growth cones in NGF-responsive nerve fibers. Semaphorin 3A stimulation also showed the opposite effects on these NGF-dependent events. Intriguingly, MMP-8 expression was upregulated by type I and III CoLs, which are substrates for this enzyme. These results suggested that MMP-8 is involved in sensory nerve growth within the interstitial CoL matrix through modulation by the axonal guidance molecules and/or extracellular matrix components. These findings provide insight into the development of pruritus involving skin nerve density.
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PMID:Matrix metalloproteinase-8 is involved in dermal nerve growth: implications for possible application to pruritus from in vitro models. 2169 83

Topical glucocorticoids are commonly applied for treatment of atopic dermatitis, and are often administered over a long period. However, itching often occurs as a rebound phenomenon after cessation of long-term glucocorticoid application. The present study was an initial trial designed to establish an animal model of glucocorticoid-induced pruritus by topical application of dexamethasone over a long period in mice with contact dermatitis. BALB/c mice with chronic allergic contact dermatitis induced by 5 weeks of repeated application of 2,4,6-trinitro-1-chlorobenzene (TNCB) were treated topically with dexamethasone for 3 weeks from 2 weeks after the elicitation of dermatitis. The effects of dexamethasone on inflammation and pruritus were evaluated by measurement of ear-swelling and scratching behavior, respectively. Significant enhancement of pruritus was confirmed after chronic application of dexamethasone. The increased frequency of scratching behavior was reduced by withdrawal of dexamethasone. On the other hand, ear-swelling was markedly ameliorated by dexamethasone treatment, but rapidly relapsed after dexamethasone withdrawal. The level of interleukin (IL)-4 mRNA in ear skin and that of IgE in serum were increased in the mice with dermatitis and reduced by dexamethasone treatment. On the other hand, the level of nerve growth factor (NGF) mRNA was slightly increased by dexamethasone treatment and remained high even after its discontinuation. It is anticipated that this novel animal model of glucocorticoid-induced pruritus will be useful for clarifying the mechanisms of the rebound phenomenon induced by chronic treatment with topical glucocorticoids, and for developing a new form of therapy.
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PMID:A novel animal model of pruritus induced by successive application of glucocorticoid to mouse skin. 2180 3

Cutaneous nerves are increased in atopic dermatitis, and itch is a prominent symptom. We studied the functional interactions between eosinophils and nerves in human and mouse skin and in culture. We demonstrated that human atopic dermatitis skin has eosinophil granule proteins present in the same region as increased nerves. Transgenic mice in which interleukin-5 (IL-5) expression is driven by a keratin-14 (K14) promoter had many eosinophils in the epidermis, and the number of nerves was also significantly increased in the epidermis. In co-cultures, eosinophils dramatically increased branching of sensory neurons isolated from the dorsal root ganglia (DRG) of mice. This effect did not occur in DRG neurons co-cultured with mast cells or with dead eosinophils. Physical contact of the eosinophils with the neurons was not required, and the effect was not blocked by an antibody to nerve growth factor. DRG neurons express eotaxin-1, ICAM-1 and VCAM-1, which may be important in the recruitment, binding, and activation of eosinophils in the region of cutaneous nerves. These data indicate a pathophysiological role for eosinophils in cutaneous nerve growth in atopic dermatitis, and suggest they may present a therapeutic target in atopic dermatitis and other eosinophilic skin conditions with neuronal symptoms such as itch.
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PMID:Eosinophils increase neuron branching in human and murine skin and in vitro. 2181 56

Nerve growth factor (NGF) was reported to be increased in the serum and skin of atopic dermatitis (AD) patients, to the extent that serum nerve growth factor levels were proposed to serve as a marker of disease severity. We studied NGF levels in the serum and dermis using skin microdialysis and attempted to correlate them with disease severity. We also examined if potential differences between morning and evening levels of NGF can explain the phenomenon of nocturnal itch. In addition, neurogenic inflammation and itch were induced using histamine iontophoresis in lesional and non-lesional skin and the effect of experimental itch on dermal NGF concentration was examined. We found that systemic (serum) and eczematous skin levels of NGF in AD are significantly lower in comparison to healthy controls. Serum NGF decreases from morning to late afternoon in both groups. Interestingly, serum NGF levels were correlated to disease severity in the morning in AD, although the NGF concentration in AD were significantly lower than in the healthy group. The local itch and neurogenic inflammation induction via experimental histamine reduced local NGF levels in the eczema and non-lesional skin in atopics, but not in the healthy controls, where it was slightly increased. The higher the clinical severity of the eczema, a significantly less pronounced effect of neurogenic inflammation on the local levels of NGF was found. The availability of measurable NGF might be reduced by a higher expression of NGF receptors. The fluctuations of NGF levels during the day suggest a complex modulation of this neurotrophin, potentially linked to stress or to an altered neurophysiological mechanism.
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PMID:A study of serum concentrations and dermal levels of NGF in atopic dermatitis and healthy subjects. 2189 40

Congenital insensitivity to pain with anhidrosis is a rare autosomal recessive hereditary disorder that is characterized by having both sensory neuropathy and anhidrosis. A 6-year-old Japanese boy presented with recurrent fever, lack of sweating, occult bone fractures and impaired pain sensation without mental retardation. Genetic analyses revealed compound heterozygous mutations in the NTRK1 gene that encodes TrkA, which is a receptor for nerve growth factor. While there were no apparent changes in the patient's dermal eccrine glands, the quantitative sudomotor axon reflex test with acetylcholine chloride revealed a complete loss of both the axon reflex-mediated and the directly activated sweat responses. On the other hand, the histamine prick test induced a normal weal response surrounded by a flare phenomenon. Notably, the patient felt both an itch sensation after histamine and a burning sensation after topical capsaicin application. Consistent with these findings, PGP9.5+ nerve fibre innervation of the papillary dermis was observed, although the fibres were completely absent around the eccrine glands. These findings suggest that there was a partial preservation of the nerve endings that express the H(1) receptor and/or TRPV1 in the upper dermis, even though there were mutations of the NTRK1 gene in this case.
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PMID:Congenital insensitivity to pain with anhidrosis: a case with preserved itch sensation to histamine and partial pain sensation. 2203 67

Pruritus is a severe symptom that is difficult to treat in atopic dermatitis patients. Red ginseng (RG), a natural medicine, has various biological activities such as anti-inflammatory effects. In this study, we examined the efficacy of RG extract (RGE) and its mechanism on experimental atopic dermatitis in mice. The effects of RGE on vascular permeability and itching were first evaluated. Histamine-induced permeability and itching were significantly inhibited by embrocation with RGE as well as diphenhydramine, an antihistamine drug. Next, we assessed the therapeutic effect of topical RGE in a mouse model of atopic dermatitis. Dermatitis was induced by repeated application of 2,4-dinitrofluorobenzene (DNFB) acetone solution to the mouse ear. The effects of tacrolimus (a calcineurin blocker), dexamethasone (a corticosteroid), and RGE on dermatitis and associated scratching behavior were compared. Repeated DNFB application caused frequent scratching behaviors and ear swelling. Topical treatment with tacrolimus, dexamethasone, and RGE for 8 days before the final challenge with DNFB significantly inhibited ear swelling. Tacrolimus and RGE significantly inhibited scratching behavior, whereas dexamethasone failed to do so. DNFB-induced nerve growth factor expression and nerve fiber extension were significantly attenuated by tacrolimus and RGE, but not by dexamethasone. RGE may have the potential for treatment of atopic dermatitis.
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PMID:Red ginseng inhibits scratching behavior associated with atopic dermatitis in experimental animal models. 2238 56

Skin of patients suffering from atopic eczema displays a higher epidermal nerve fiber density, associated with neurogenic inflammation and pruritus. Using an in vitro coculture system, allowing a spatially compartmented culture of somata from porcine dorsal root ganglion neurons and human primary skin cells, we investigated the influence of dermal fibroblasts and keratinocytes on neurite outgrowth. In comparison with dermal fibroblasts, keratinocytes induced more branched and less calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers. By adding neutralizing antibodies, we showed that nerve growth factor (NGF) and glial cell-line-derived neurotrophic factor (GDNF) are pivotal neurotrophic factors of skin cell-induced neurite outgrowth. Keratinocytes and dermal fibroblasts secreted different ratios of neurotrophic factors, influencing morphology and CGRP immunoreactivity of neurites. To investigate changes of the peripheral nervous system in the pathogenesis of atopic eczema in vitro, we analyzed neurite outgrowth mediated by atopic skin cells. Atopic keratinocytes produced elevated levels of NGF and mediated an increased outgrowth of CGRP-positive sensory fibers. Our results demonstrate the impact of dermal fibroblasts and keratinocytes on skin innervation and emphasize the role of keratinocytes as key players of hyperinnervation in atopic eczema.
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PMID:Atopic keratinocytes induce increased neurite outgrowth in a coculture model of porcine dorsal root ganglia neurons and human skin cells. 2241 69

Pruritus is a common symptom of psoriasis, which affects quality of life. This symptom accompanies the hyper-innervation of sensory C-fibres in psoriatic lesions. Two extracellular molecules, nerve growth factor (NGF) and semaphorin-3A, regulate C-fibre extension. In this study, the expression levels of these 2 molecules in biopsy specimens from psoriatic and healthy skin were quantified by immunohistochemistry and quantitative reverse-transcription PCR. Semaphorin-3A expression was lower in the psoriatic samples compared with the healthy samples, whereas NGF was higher. C-fibre innervation in the epidermis was also increased in psoriatic skin. Semaphorin-3A mRNA expression was negatively correlated with itch intensity and severity of psoriasis. We propose that decreased semaphorin-3A and increased NGF expression levels may trigger the outgrowth of C-fibres, leading to pruritus.
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PMID:Decreased expression of semaphorin-3A, a neurite-collapsing factor, is associated with itch in psoriatic skin. 2256 12


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