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ABSTRACT: Previous PET and fMRI brain imaging studies targeting neural networks processing itch sensation have used histamine as the sole itch inducer. In contrast with histamine, cowhage-induced itch is mediated via proteinase activated receptors PAR2 and is transmitted through a separate spinothalamic pathway, therefore imaging the brain activation evoked by cowhage could provide further insight into central processing of itch. We report for the first time a functional MRI Arterial Spin Labeling (ASL) study of neuronal processing of itch induced by cowhage, analyzed in contrast with histamine-induced itch. We also explored the brain responses induced by histamine and cowhage combined in a tight sequence. The results of our analyses obtained in a group of 15 healthy volunteers suggested that cowhage and histamine co-activated a core group of brain structures, while also revealing notable differences. Core areas activated by both stimuli were found in the thalamus, primary and secondary somatosensory cortices, posterior parietal cortex, superior and middle temporal cortices, PCC, ACC, precuneus and cuneus. Cowhage induced a notably distinct and more extensive involvement of the insular cortex, claustrum, basal ganglia, putamen, thalamic nuclei and pulvinar. The differences observed between these two itch modalities were investigated to determine the impact of quantitative versus qualitative factors, and correlations between itch intensity and the patterns in brain activation were explored. Our analysis revealed that the most significant differences between cowhage and histamine itch were not affected by stimulus intensity, although a subset of regions displayed activations which were intensity-dependent. The combined application of cowhage and histamine highlighted the role of insula and claustrum in the processing of both itch modalities in the same time. The present results suggest the existence of overlapping but also distinct neuronal networks processing these two different types of itch.
NeuroImage 11/2011; 59(4):3611-23. · 5.89 Impact Factor
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ABSTRACT: 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.
Neuropeptides 09/2011; 45(6):417-22. · 1.55 Impact Factor
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ABSTRACT: Histamine is the prototypical pruritogen used in experimental itch induction. However, in most chronic pruritic diseases, itch is not predominantly mediated by histamine. Cowhage-induced itch, on the other hand, seems more characteristic of itch occurring in chronic pruritic diseases.
We tested the validity of cowhage as an itch-inducing agent by contrasting it with the classical itch inducer, histamine, in healthy subjects and atopic dermatitis (AD) patients. We also investigated whether there was a cumulative effect when both agents were combined.
Fifteen healthy individuals and fifteen AD patients were recruited. Experimental itch induction was performed in eczema-free areas on the volar aspects of the forearm, using different itch inducers: histamine, cowhage and their combination thereof. Itch intensity was assessed continuously for 5.5 minutes after stimulus application using a computer-assisted visual analogue scale (COVAS).
In both healthy and AD subjects, the mean and peak intensity of itch were higher after the application of cowhage compared to histamine, and were higher after the combined application of cowhage and histamine, compared to histamine alone (p<0.0001 in all cases). Itch intensity ratings were not significantly different between healthy and AD subjects for the same itch inducer used; however AD subjects exhibited a prolonged itch response in comparison to healthy subjects (p<0.001).
Cowhage induced a more intense itch sensation compared to histamine. Cowhage was the dominant factor in itch perception when both pathways were stimulated in the same time. Cowhage-induced itch is a suitable model for the study of itch in AD and other chronic pruritic diseases, and it can serve as a new model for testing antipruritic drugs in humans.
PLoS ONE 01/2011; 6(3):e17786. · 4.09 Impact Factor
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ABSTRACT: Burning mouth syndrome (BMS) is a chronic orofacial pain syndrome that occurs in middle-aged and postmenopausal women and poses a therapeutic challenge to dermatologists and dentists. It has been suggested previously that BMS is a small-fiber neuropathy.
This study was designed to examine thermal sensory and pain thresholds in the oral mucosa and chin, both innervated by the trigeminal nerve, in patients with BMS, as well as in healthy controls. In addition, the study proposed to examine whether there are any differences in oral thermal and pain sensations between the advanced age group, where BMS is prevalent and a younger group.
Thermal and pain thresholds of BMS patients did not differ significantly from those of healthy subjects. An increased threshold to thermal warmth and a decreased threshold for cold sensation for the tongue and chin were noted in the group over 50 years in comparison with younger subjects, indicating a decreased sensitivity to thermal stimuli. The group over 50 years of age displayed an increased sensitivity to cold pain and a decreased sensitivity to hot pain in the tongue (compared with the chin).
BMS patients do not demonstrate alterations in thermal and pain detection, thus failing to support a true small nerve neuropathy in this condition.
Skin Research and Technology 01/2011; 17(2):196-200. · 1.71 Impact Factor
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ABSTRACT: Serine proteases and some cathepsins are present in the stratum corneum. They are known to play a significant role in the pathophysiological mechanism of several dermatological conditions (e.g. atopic dermatitis) and in the induction of itch. Tape stripping of skin is a simple technique used in the investigation of skin barrier function and in the penetration of topically applied drugs. Herein, we show that CE, under stacking conditions, is a well-suited technique to measure the proteolytic activity of enzymes in the stratum corneum. Disks of about 6 mm (id) were cut from adhered tapes and submerged directly in a buffer containing the appropriate peptide substrate. After incubation, the split peptides were separated and detected directly by CE at 214 nm in a borate buffer. The esterase activity on N-benzoyl-tyrosine ethyl ester and the amidase activity on succinyl-Ala-Ala-Pro-Phe-p-nitroanilide and the splitting of hemoglobin were detected by CE. The esterase activity was the highest when compared to the proteolytic activities. Skin scratching increased the enzymatic activity adhered to the tapes. The CE offered over the traditional end-point colorimetric methods the ability to measure the low enzymatic activity and the ability to detect the released peptides directly. This technique is simple, non-invasive, easy to perform and uses non-expensive substrates. It can be useful in quantifying cathepsins and serine proteases in the skin.
Electrophoresis 10/2010; 31(19):3346-51. · 3.30 Impact Factor
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ABSTRACT: Atopic dermatitis is a stress-responsive disorder that involves the autonomic nervous system. The current study used heart rate variability to examine the effect of itch, scratching and mental stress in atopic patients with moderate to severe disease. Twenty-one patients with active disease and 24 healthy volunteers participated in the study. Heart rate variability measurements were taken at 5 min intervals at rest and after each of 3 acute stress tests, which included histamine-induced itch at the forearm, scratching around the itch site, and the Trier Social Stress Test. Atopic patients displayed a higher heart rate than healthy controls in all 4 experimental settings, which was statistically significant using Cohen's delta analysis. The very low frequency component of the power spectrum, indicative of sympathetic activity, showed a 200% increase after scratching in patients with atopic dermatitis. The high frequency component, reflecting parasympathetic tone, responded swiftly to itch and scratching in healthy controls, but displayed a limited adaptability in atopic dermatitis. This study supports the concept that atopic dermatitis is a stress-responsive disorder and involves autonomic nervous system dysfunction. Atopic subjects exhibited an overactive sympathetic response to itch and scratching, while the parasympathetic tone was persistently and rigidly elevated, showing a lack of adaptability in response to stress.
Acta Dermato-Venereologica 07/2010; 90(4):354-61.
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ABSTRACT: Capsaicin and its receptor, TRPV1, occupy a central place in current neurophysiological studies regarding pain transmission and have opened new avenues for understanding the role of transient receptor potential (TRP) receptors in itch processing. Substantial efforts in drug discovery are at present directed at vanilloid receptors for finding new remedies for pain and itch.
We provide an overview of the major clinical indications of capsaicin, primarily targeting pain and itch of various origins, with an emphasis on the usefulness of capsaicin in treating pruritus and dermatological conditions. In particular, we cover the most relevant findings in recent years, from 2000 onward (although seminal discoveries and studies are discussed irrespective of their date of publication if deemed essential for understanding capsaicin's actions).
Readers are offered a broad perspective on the areas of clinical application of capsaicin, emphasizing its usefulness in the treatment of neurophatic pain and pruritus of various origins.
Capsaicin has been proven a truly exciting molecule and remains a valuable drug for alleviating pain and itch, widely surpassing its role as a simple spicy ingredient.
Expert Opinion on Pharmacotherapy 06/2010; 11(8):1359-71. · 3.20 Impact Factor
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ABSTRACT: Itch, the hallmark of atopic dermatitis, has a significant impact on quality of life for patients with this disease. Various central and peripheral mediators have been suggested to play a role in the pathophysiology of atopic eczema itch. Significant cross-talk occurs among stratum corneum, keratinocytes, immune cells, and nerve fibers, which are in close proximity to one another and induce itch. The impaired barrier function associated with the itch-scratch cycle further augments this vicious cycle. Recent advances in our understanding of itch pathophysiology shed light on peripheral and central neural sensitization of nerve fibers that contribute significantly to itch in atopic dermatitis. Recently, several new mediators have been described as associated with itch in atopic dermatitis, including serine proteases, interleukin 31, and nerve growth factor. This review covers the peripheral and central mechanisms and mediators involved in pathogenesis of itch in atopic dermatitis.
Current Allergy and Asthma Reports 08/2008; 8(4):306-11. · 2.50 Impact Factor
