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Abstract: Pruritus is an unpleasant sensation leading to the desire to scratch. It is the most common symptom in dermatology, and various skin and systemic diseases can be associated with the presence of itching. Pruritus may also be provoked by numerous drugs. Although the exact epidemiologic data are still absent, it is generally accepted that elderly people frequently suffer from pruritus, and the problem of itching in this population remains a challenge for clinicians. The elderly often complain of numerous comorbidities that complicate the determination of the cause of pruritus, as well as its treatment. Physical and mental deprivation may complicate proper assessment of pruritus severity and negatively impair compliance with complex antipruritic therapies. Taking also into account heterogeneity of possible causes of pruritus, every patient with pruritus must be handled individually, regarding the diagnostic procedures and antipruritic therapy. [ABSTRACT FROM AUTHOR]

Abstract: Background and objectives: The most abundant malignant brain tumor in human is glioblastoma and patients with this type of tumor have a poor prognosis with high mortality. Glioblastoma are characterized particularly by fast growth and a dependence on blood vessel formation for survival. Cannabinoids (CBs) inhibit tumor growth by inducing apoptosis of tumor cells and impairing tumor angiogenesis. The distribution of CB1 and CB2 receptors in glioblastoma and associated endothelial vessels is still unknown. Methods: Tissue samples were collected consecutively after neurosurgery of 19 patients suspected glioblastoma and examined immunohistochemically for CB1 and CB2 receptor expression. Vessel endothelial cells of the sections were immunocytochemically identified by using a primary antibody against PECAM-1. Double labelling was performed for CB receptors and endothelial cells of the vessels by DAPI staining. Results: In endothelia of control tissue, about 24% and 45% of the cells were positive for CB1 and CB2 receptors. In glioblastoma endothelial cells, CB1 and CB2 receptors were present in about 38% and 54% of the cells respectively. In comparison to CB1, an elevated CB2 receptor expression was identified in glioblastoma. Conclusions: The abundant expression and distribution of CB2 receptors in glioblastoma and particularly endothelial cells of glioblastoma indicate that impaired tumor growth in presence of CB may be associated with CB2 activation. Selective CB2 agonists might become important targets attenuating vascular endothelial growth factor (VEGF) signalling and thereby diminishing neoangiogenesis and glioblastoma growth. [Copyright &y& Elsevier]

Summary: Background:: Cannabinoid receptors mediate the psychopharmacological action of marijuana and have been localized in the central and peripheral nervous system as well as on cells of the immune system. Objective:: Up to now, two cannabinoid receptors (CB1 and CB2) have been cloned and recent studies on animal tissue gave evidence for the presence of cannabinoid receptors in the skin. Methods:: In the present immunohistochemical investigation we determined the precise localization of CB1 and CB2 in sections of human skin and in one case of mastocytosis. Results:: CB1 and CB2 immunoreactivity was observed in cutaneous nerve fiber bundles, mast cells, macrophages, epidermal keratinocytes, and the epithelial cells of hair follicles, sebocytes and eccrine sweat glands. In epidermal keratinocytes, hair follicle and sebaceous glands, CB1 and CB2 were distributed in a complementary fashion. Double-immunostaining with an anti-CGRP antibody suggested the presence of cannabinoid receptors on small afferent peptidergic nerves. Conclusion:: The abundant distribution of cannabinoid receptors on skin nerve fibers and mast cells provides implications for an anti-inflammatory, anti-nociceptive action of cannabinoid receptor agonists and suggests their putatively broad therapeutic potential. [Copyright &y& Elsevier]

Opioid peptides are endogenous neuromodulators that play a major role in the nociceptive pathway by interacting with opioid receptors. So far, four opioid receptors (μ-, δ-, κ-, orphan-receptor) have been cloned with a wide distribution in the central and peripheral nervous system. In the present study, we give first evidence for the presence of the μ-opioid receptor (MOR) isoform 1A in nerve fibers of human skin. Immunohistochemical analysis revealed MOR immunoreactivity to be present in dermal and epidermal nerve fibers. Double-immunofluorescence staining revealed that MOR is present on calcitonin gene-related protein (CGRP)-positive sensory nerve fibers, while autonomic nerves of blood vessels, hair follicles, or skin glands were negative. In diseased skin such as psoriasis vulgaris, atopic dermatitis, and prurigo nodularis, distribution of MOR 1A immunoreactivity was similar to that of normal skin. These findings expand our knowledge about a direct regulatory role of cutaneous opioid receptors in the skin. Thus, peripheral cutaneous opioid receptors may be involved in the transmission of pain and pruritus, respectively. This is supported by previous observation that opioid receptor antagonists may significantly diminish experimentally evoked histamine-induced itch of the skin. Together, our findings contribute to the understanding of the high antipruritic potency of opioid receptor antagonists in various skin and systemic diseases. [Copyright &y& Elsevier]

The article provides information on the 3rd International Workshop for the Study of Itch which was held on September 2005 in Heidelberg, Germany. It was participated by 200 scientists and physicians who were interested in issues related to itch. Topics covered relevant neurophysiological aspects, localized and systematic itch, human and animal itch and pyschosocial views of itch.

• Chronic pruritus (CP) is hard to treat and often refractory to conventional drugs. • Higher understanding of the pathophysiology led to identification of new targets. • Promising novel agents for CP are in phase II and phase III trials. • Guidelines offer approach to current management of CP. Chronic pruritus is a highly prevalent, debilitating disease, which is often refractory to conventional therapies. A step-wise, guideline-driven approach should be adopted in the management of these patients. Emollients as well as topical corticosteroids if appropriate should be initiated whilst looking for the cause underlying the pruritus. If these measures fail, and the origin of the pruritus remains unknown, cannot be treated or does not respond to therapy, systemic therapies as for example gabapentinoids, antidepressants, mu-opioid-receptor antagonists or, in case of inflammatory conditions, immunosuppressive drugs should be recommended. Novel agents, especially systemic monoclonal antibodies, neurokinin-1 receptor antagonists and opioid receptor modulators, are promising in providing relief in refractory cases. [ABSTRACT FROM AUTHOR]

Abstract Chronic pruritus (CP) is a bothersome symptom of many different diseases and is often associated with psychosomatic and psychiatric comorbidity. This review gives an overview of psychologic factors that influence the perception and modulation of pruritus based on the well-known biopsychosocial model. Not only psychic comorbidities, such as anxiety and depression, play an important role in the etiology and perception of pruritus, but also internal factors, including personality, mentalization, suggestibility, and external factors, as well as stress. Expectations concerning the intensity of pruritus can also play a role in itch perception that can be modulated by cognitions and behavior of the patient. Obsessive rituals of scratching and skin manipulation with instruments present challenges in the treatment of CP. Initial studies on the efficacy of psychotherapeutic approaches to different problems, such as scratching, comorbidity, or stress-associated itch, show that these might be very useful additions to the multidisciplinary treatment of pruritus. [ABSTRACT FROM AUTHOR]

Neuropathic pruritus conditions arise from structural and/or functional damage of the peripheral or central nervous system. Novel findings of pruritus specific mediators and pathways strengthen the specificity theory of pruritus transmission, however electrophysiological studies suggest that focal activation of nociceptors and distinct discharge patterns of primary afferents also contribute to the development of the sensation of pruritus. A complex interplay between excitatory and inhibitory interneurons at spinal level, non-neuronal cells and descending modulation from upper centers contributes to neuronal sensitization and clinically to the chronicity of pruritus, as well as accompanying phenomena such as alloknesis and hyperknesis. Several topical, systemic and non-pharmacological therapeutic approaches directed at distinct targets are currently available. [ABSTRACT FROM AUTHOR]

The underlying mechanisms of chronic pruritus (CP), which is often very debilitating for patients, are still not well understood. Over the past few years, peripheral and central mechanisms involving different classes of pruriceptive and nociceptive neuron (e.g., C- and Aδ-fibers), immune cells (e.g., eosinophils, basophils, Th1, Th2, and mast cells) and epithelial cells (e.g., keratinocytes) have been investigated. Based on these, numerous promising target-specific therapies are under development. In this review, we highlight the cells, key mediators, and receptors involved in itch perception and CP, and conclude by summarizing the therapies developed for these conditions. Unmyelinated C- and thin myelinated Aδ-fibers in the epidermis and papillary dermis are involved in cutaneous sensation of pruritus. Aβ-fibers are involved in central sensitization processes leading to alloknesis in CP. Cutaneous neuroanatomy is altered in PC, with fewer fibers crossing the basement membrane. A disturbed crosstalk between neural, inflammatory, and skin cells is characteristic of CP. Promising therapies for CP involve anti-inflammatory and neuromodulatory approaches. [ABSTRACT FROM AUTHOR]

Many lines of evidence indicate that the activity of sebaceous glands can be modulated by neuropeptides. Direct evidence in man, however, is still missing. We show that SZ95 sebocytes, an immortalized human sebaceous gland cell line, express receptors for α-melanocyte-stimulating hormone. Reverse transcription polymerase chain reaction with primers against the five melanocortin receptors and immunofluorescence studies using an antibody directed against a peptide corresponding to the amino acids 2–18 of the human melanocortin-1 receptor disclosed specific transcripts and immunoreactivity for melanocortin-1 receptor in these cells. Melanocortin-1 receptor expression was confirmed in sebocytes of normal human skin by immunohistochemistry. In contrast, no immunostaining for the melanocortin-5 receptor could be detected in sebocytes in situ , in accordance with the lack of specific transcripts for this melanocortin receptor in SZ95 sebocytes. As cytokines play an important role in the recruitment of inflammatory cells in acne and related disorders and α-melanocyte-stimulating hormone exerts immunomodulatory effects in many other cell types, we investigated the effect of α-melanocyte-stimulating hormone on interleukin-8 secretion by SZ95 sebocytes. Treatment with interleukin-1β resulted in a marked increase in interleukin-8 release that was partially blocked by coincubation with α-melanocyte-stimulating hormone in a dose-dependent manner. Taken together, we show here that the melanocortin-1 receptor is expressed in vitro and in situ in human sebocytes. By modulating interleukin-8 secretion, α-melanocyte-stimulating hormone may act as a modulator of inflammatory responses in the pilosebaceous unit. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is an inflammatory, pruritic, chronic or chronically relapsing skin disease that typically begins in early childhood and is occurring frequently in families with other atopic diseases (bronchial asthma and/or allergic rhino-conjunctivitis). Thanks to immunological and neurobiological research, the era of new treatments is coming as well as it occurred with psoriasis 15 years ago. Many treatments targeting cytokines (IL-4, IL-13, IL-31, TSLP) or neurotransmitters (substance P, opioids) or their respective receptors as well as phosphodiesterase-4 or the Jak/Stat pathways are under development. Antagonists of cytokines and anti-jak have promising effects on pruritus while it is more difficult to discriminate the effects of other drugs from the placebo effect on itch, which is known to be high. [ABSTRACT FROM AUTHOR]

Objectives The first objective of this study is to evaluate the impact of integrating a single-source system into the routine patient care documentation workflow with respect to process modifications, data quality and execution times in patient care as well as research documentation. The second one is to evaluate whether it is cost-efficient using a single-source system in terms of achieved savings in documentation expenditures. Methods We analyzed the documentation workflow of routine patient care and research documentation in the medical field of pruritus to identify redundant and error-prone process steps. Based on this, we established a novel documentation workflow including the x4T (exchange for Trials) system to connect hospital information systems with electronic data capture systems for the exchange of study data. To evaluate the workflow modifications, we performed a before/after analysis as well as a time–motion study. Data quality was assessed by measuring completeness, correctness and concordance of previously and newly collected data. A cost–benefit analysis was conducted to estimate the savings using x4T per collected data element and the additional costs for introducing x4T. Results The documentation workflow of patient care as well as clinical research was modified due to the introduction of the x4T system. After x4T implementation and workflow modifications, half of the redundant and error-prone process steps were eliminated. The generic x4T system allows direct transfer of routinely collected health care data into the x4T research database and avoids manual transcription steps. Since x4T has been introduced in March 2012, the number of included patients has increased by about 1000 per year. The average entire documentation time per patient visit has been significantly decreased by 70.1% (from 1116 ± 185 to 334 ± 83 s). After the introduction of the x4T system and associated workflow changes, the completeness of mandatory data elements raised from 82.2% to 100%. In case of the pruritus research study, the additional costs for introducing the x4T system are €434.01 and the savings are 0.48ct per collected data element. So, with the assumption of a 5-year runtime and 82 collected data elements per patient, the amount of documented patients has to be higher than 1102 to create a benefit. Conclusion Introduction of the x4T system into the clinical and research documentation workflow can optimize the data collection workflow in both areas. Redundant and cumbersome process steps can be eliminated in the research documentation, with the result of reduced documentation times as well as increased data quality. The usage of the x4T system is especially worthwhile in a study with a large amount of collected data or a high number of included patients. [ABSTRACT FROM AUTHOR]

As the outermost barrier of the body, the skin is exposed to multiple environmental factors, including temperature, humidity, mechanical stress, and chemical stimuli such as odorants that are often used in cosmetic articles. Keratinocytes, the major cell type of the epidermal layer, express a variety of different sensory receptors that enable them to react to various environmental stimuli and process information in the skin. Here we report the identification of a novel type of chemoreceptors in human keratinocytes, the olfactory receptors (ORs). We cloned and functionally expressed the cutaneous OR, OR2AT4, and identified Sandalore, a synthetic sandalwood odorant, as an agonist of this receptor. Sandalore induces strong Ca2+ signals in cultured human keratinocytes, which are mediated by OR2AT4, as demonstrated by receptor knockdown experiments using RNA interference. The activation of OR2AT4 induces a cAMP-dependent pathway and phosphorylation of extracellular signal-regulated kinases (Erk1/2) and p38 mitogen-activated protein kinases (p38 MAPK). Moreover, the long-term stimulation of keratinocytes with Sandalore positively affected cell proliferation and migration, and regeneration of keratinocyte monolayers in an in vitro wound scratch assay. These findings combined with our studies on human skin organ cultures strongly indicate that the OR 2AT4 is involved in human keratinocyte re-epithelialization during wound-healing processes. [ABSTRACT FROM AUTHOR]

Abstract: Background: In prurigo nodularis (PN), an increase in the density of dermal substance P-positive (SP+) sensory nerve fibers has been demonstrated. In addition, the density of sympathetic nerve fibers is unchanged. Objective: We aimed to investigate the density and balance of sensory and sympathetic dermal nerves in pruritus on normally appearing skin in comparison to PN. Methods: In a parallel investigation in lesional and non-lesional skin routine histological and immunofluorescence staining against SP and tyrosine hydroxylase (TH) were performed. Results: We found an increased density of dermal SP+ nerve fibers in PN and also in pruritus relative to sympathetic nerve fibers in affected areas compared to the unaffected site. The density of SP+ and TH+ nerves did not correlate with clinical parameters such as itch quality, duration or intensity. Sparse lymphocytic infiltration as found in affected pruritus skin may be a source of nerve growth factor and explain the hyperinnervation. Conclusion: Similar to the situation in PN, chronic pruritus lesions also demonstrate a preponderance of SP+ sensory nerve fibers relative to sympathetic nerve fibers, which probably acts as a causal pro-inflammatory signal in development of pruritus. These findings suggest new therapeutic approaches in patients with chronic pruritus. [Copyright &y& Elsevier]

Matriptase (membrane-type serine proteinase) was reported to play a role in nonmelanoma skin cancer progression. Moreover, it was shown to stimulate proteinase-activated receptor-2 (PAR2) in vitro. Hepatocyte growth factor activator inhibitor-1 (HAI-1), the matriptase inhibitor, is an important regulator of enzyme activity. Therefore, the aim of this study was to elucidate the putative role of matriptase, HAI-1, and PAR2 in normal human skin, as well as in basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs). In normal human epidermis, PAR2 colocalized with matriptase and HAI-1. Immunoreactivity of all proteins was found to be diminished in BCCs. Likewise, PAR2 immunoreactivity was significantly decreased, whereas matriptase immunoreactivity was enhanced with SCC progression. We could also show that matriptase was complexed to HAI-1 in normal human skin, whereas in SCCs, the enzyme was present in an unassociated form. Both a specific peptide agonist for PAR2 and the proteinase domain of matriptase were able to induce intracellular calcium mobilization and inhibition of proliferation in cultured HaCaT keratinocytes. In conclusion, our results suggest that PAR2 is a substrate for matriptase in human skin in vivo. Deregulation of these proteins delineates SCC progression.Journal of Investigative Dermatology (2009) 129, 1816–1823; doi:10.1038/jid.2008.449; published online 26 February 2009 [ABSTRACT FROM AUTHOR]

The proteinase-activated receptor PAR2 has been demonstrated to modulate tumor growth, invasion and metastasis in various tissues. However, the role of PAR2 in cutaneous cancerogenesis is still unknown. Here we could show a protective role of PAR2 in the development of epidermal skin tumors: we established a mouse skin tumor model using chemically induced carcinogenesis. Tumors started to appear after eight weeks. After 13 weeks, PAR2-deficient mice showed a significantly increased number of skin tumors (14 per animal on the average) in contrast to the wild type (eight tumors per mouse). Analysis of possible signal transduction pathways activated upon PAR2 stimulation in HaCaT keratinocytes showed an involvement of extracellular signal-regulated kinase 1/2 and profound epidermal growth factor receptor transactivation, leading to secretion of the tumor-suppressing factor transforming growth factor-β1. Thus, our results provide early experimental evidence for a tumor-protective role of PAR2.Journal of Investigative Dermatology (2007) 127, 2245–2252; doi:10.1038/sj.jid.5700847; published online 3 May 2007 [ABSTRACT FROM AUTHOR]

Suppression of collagen synthesis is a major therapeutic goal in the treatment of fibrotic disorders. We show here that α-melanocyte-stimulating hormone (α-MSH), a neuropeptide well known for its pigment-inducing capacity, modulates collagen synthesis and deposition. α-MSH in vitro suppresses the synthesis of collagen types I, III, and V and down-regulates the secretion of procollagen type I C-terminal peptide (PICP) in human dermal fibroblasts treated with the fibrogenic cytokine transforming growth factor-β1 (TGF-β1). α-MSH did not interfere with TGF-β1 signaling, because TGF-β1-induced expression of collagen mRNA was not affected, implying a posttranscriptional mechanism. Human dermai fibroblasts in vitro express a high affinity binding site for MSH, which was identified by reverse transcription PCR and immunofluorescence analysis as the melanocortin-1 receptor (MC-1R). Immunohistochemical studies on normal adult human skin confirmed MC-IR expression in distinct dermal fibroblastic cells. The MC-1R on fibroblasts appears to be functionally relevant because α-MSH increased the amount of intracellular cAMP, and coincubation with a synthetic peptide corresponding to the human Agouti signaling protein abrogated the inhibition of TGF-β1-induced PICP secretion by α-MSH. To assess the in vivo relevance of these findings, a mouse model was used in which dermal fihrosis was induced by repetitive intracutaneous injections with TGF-β1. The inductive activity of TGF-β1 on collagen deposition and the number of dermal cells immunoreactive for vimentin and α-smooth muscle actin was significantly suppressed by injection of α-MSH. Melanocortins such as α-MSH may therefore represent a novel class of modulators with potential usefulness for the treatment of fibrotic disorders. [ABSTRACT FROM AUTHOR]