Alexandru D. P. Papoiu

A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch

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.

Contagious Itch in Humans. A Study of Visual “Transmission” of Itch in Atopic Dermatitis and Healthy Subjects

Background  Anecdotal evidence suggests that ‘contagious’ itch occurs in daily life when we see other people itch and scratch. This phenomenon has not previously been studied systematically, and factors which can amplify itch perception were unknown.

Cowhage-Induced Itch as an Experimental Model for Pruritus. A Comparative Study with Histamine-Induced Itch

Background 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. Objectives 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. Methods 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). Results 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). Conclusions 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.

Effect of Itch, Scratching and Mental Stress on Autonomic Nervous System Function in Atopic Dermatitis

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 Cohens 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.

Topical capsaicin. The fire of a 'hot' medicine is reignited

Importance of the field: 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. Areas covered in this review: 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 capsaicins actions). What the reader will gain: 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. Take home message: 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.

Brain's reward circuits mediate itch relief. a functional MRI study of active scratching.

Previous brain imaging studies investigating the brain processing of scratching used an exogenous intervention mimicking scratching, performed not by the subjects themselves, but delivered by an investigator. In real life, scratching is a conscious, voluntary, controlled motor response to itching, which is directed to the perceived site of distress. In this study we aimed to visualize in real-time by brain imaging the core mechanisms of the itch-scratch cycle when scratching was performed by subjects themselves. Secondly, we aimed to assess the correlations between brain patterns of activation and psychophysical ratings of itch relief or pleasurability of scratching. We also compared the patterns of brain activity evoked by self-scratching vs. passive scratching. We used a robust tridimensional Arterial Spin Labeling fMRI technique that is less sensitive to motion artifacts: 3D gradient echo and spin echo (GRASE) - Propeller. Active scratching was accompanied by a higher pleasurability and induced a more pronounced deactivation of the anterior cingulate cortex and insula, in comparison with passive scratching. A significant involvement of the reward system including the ventral tegmentum of the midbrain, coupled with a mechanism deactivating the periaqueductal gray matter (PAG), suggests that itch modulation operates in reverse to the mechanism known to suppress pain. Our findings not only confirm a role for the central networks processing reward in the pleasurable aspects of scratching, but also suggest they play a role in mediating itch relief.

Ethnic differences in pain, itch and thermal detection in response to topical capsaicin: African Americans display a notably limited hyperalgesia and neurogenic inflammation

Background  Topical application of capsaicin commonly produces burning, stinging and itching as well as hyperalgesia to heat stimuli via activation of transient receptor potential vanilloid subtype 1.

Voxel-based morphometry and arterial spin labeling fMRI reveal neuropathic and neuroplastic features of brain processing of itch in end-stage renal disease.

Pruritus of end-stage renal disease (ESRD) is a multifactorial symptom of complex etiology not yet fully understood. In this study we have investigated the cerebral perfusion patterns at rest in ESRD patients on hemodialysis, compared with those in healthy volunteers. We have also studied the brain responses evoked by experimental itch induction in ESRD, after stimulating the two distinct histamine and cowhage itch pathways, and compared them with the responses evoked in healthy volunteers. To identify potential structural alterations in ESRD patients compared with a group of age-matched healthy volunteers, we calculated the density of gray matter for the entire brain using a voxel-based morphometric analysis. Our results indicated that gray matter density was significantly reduced in ESRD patients in the frontal, parietal, temporal, and occipital cortices, as well as in the S1, precuneus, and insula, whereas the brain stem, hippocampus, amygdala, midcingulate cortex, and nucleus accumbens displayed an increased gray matter density. Functionally, we found a significantly higher brain perfusion at baseline associated with ESRD pruritus in the anterior cingulate, insula, claustrum, hippocampus, and nucleus accumbens. The brain responses evoked by cowhage itch, which are mediated by protease-activated receptors (PAR2), displayed significant differences compared with responses in healthy individuals and were correlated with perceived itch intensity in a dual, complex manner. The inverse correlations in particular suggested that a negative feedback mechanism modulated itch intensity, when elicited in a preexistent chronic itch background.

A study of serum concentrations and dermal levels of NGF in atopic dermatitis and healthy subjects

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.

Overexpression of the gastrin-releasing peptide in cutaneous nerve fibers and its receptor in the spinal cord in primates with chronic itch.

Leigh A. Nattkemper1,2, Zhong-Qiu Zhao5, Anna J. Nichols6, Alexandru D.P. Papoiu1, Carol A. Shively4, Zhou-Feng Chen5, and Gil Yosipovitch1,2,3,* 1Department of Dermatology, Wake Forest University School of Medicine, Winston Salem, NC, USA 2Department of Neurobiology & Anatomy, University Wake Forest School of Medicine, Winston Salem, NC, USA 3Department of Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA 4Department of Comparative Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA 5Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, USA 6Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA