Journal Club 2015.10.30

J Neurosci. 2011 May 18;31(20):7563-7. doi: 10.1523/JNEUROSCI.1192-11.2011.

BAM8-22 peptide produces itch and nociceptive sensations in humans independent of histamine release.

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Abstract

Chronic itch accompanying many dermatological, neurological, and systemic diseases is unresponsive to antihistamines. Our knowledge of endogenous chemicals that evoke histamine-independent itch and their molecular targets is very limited. Recently it was demonstrated in behavioral and cellular experiments that bovine adrenal medulla 8-22 peptide (BAM8-22), a proteolytically cleaved product of proenkephalin A, is a potent activator of Mas-related G-protein-coupled receptors (Mrgprs), MrgprC11 and hMrgprX1, and induces scratching in mice in an Mrgpr-dependent manner. To study the sensory qualities that BAM8-22 evokes in humans, we tested the volar forearm of 15 healthy volunteers with heat-inactivated cowhage spicules previously soaked in the peptide. BAM8-22 produced itch in each subject, usually accompanied by sensations of pricking/stinging and burning. The sensations were occasionally accompanied by one or more mechanically evoked dysesthesias, namely alloknesis, hyperknesis, and/or hyperalgesia, but no wheal or neurogenic flare in the skin surrounding the application site. The inactive truncated peptide BAM8-18 produced weak or no sensations. Pretreatment of the tested skin with an antihistamine cream (doxepin) inhibited histamine-induced sensations, dysesthesias, and skin reactions but not the sensations and dysesthesias evoked by BAM8-22. We show that BAM8-22 produces itch and nociceptive sensations in humans in a histamine-independent manner. Thus, BAM8-22 may be an endogenous itch mediator that activates, in humans, MrgprX1, a novel target for potential anti-itch treatments.

Journal Club 2015.10.23

By onlynice20

Lysophosphatidic Acid Is a Potential Mediator of Cholestatic Pruritus

1-s2.0-S0016508510007377-main

ANDREAS E. KREMER,* JOB J. W. W. MARTENS,* WIM KULIK,‡ FRANZISKA RUËFF,§ EDITH M. M. KUIPER,? HENK R. VAN BUUREN,? KAREL J. VAN ERPECUM,¶ JURATE KONDRACKIENE,# JESUS PRIETO,** CHRISTIAN RUST,‡‡ VICTORIA L. GEENES,§§ CATHERINE WILLIAMSON,§§ WOUTER H. MOOLENAAR,?? ULRICH BEUERS,* and RONALD P. J. OUDE ELFERINK* *Tytgat Institute for Liver and Intestinal Research and ‡Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; §Departments of Dermatology and Allergology, University of Munich, Munich, Germany; ‡‡Internal Medicine II – Grosshadern, University of Munich, Munich, Germany; ?Department of Gastroenterology & Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; ¶Department of Gastroenterology and Hepatology, University Medical Center, Utrecht, The Netherlands; #Department of Gastroenterology, Kaunas University of Medicine, Kaunas, Lithuania; **Department of Medicine and Liver Unit, Clinica Universitaria, Medical School and Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; §§Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Imperial College London, London, England; and ?Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

BACKGROUND & AIMS: Pruritus is a common and disabling symptom in cholestatic disorders. However, its causes remain unknown. We hypothesized that potential pruritogens accumulate in the circulation of cholestatic patients and activate sensory neurons.
METHODS: Cytosolic free calcium ([Ca2?]i) was measured in neuronal cell lines by ratiometric fluorometry upon exposure to serum samples from pruritic patients with intrahepatic cholestasis of pregnancy (ICP), primary biliary cirrhosis (PBC), other cholestatic disorders, and pregnant, healthy, and nonpruritic disease controls. Putative [Ca2?]i-induc- ing factors in pruritic serum were explored by analytical techniques, including quantification by high-performance liquid chromatography/mass spectroscopy. In mice, scratch activity after intradermal pruritogen injection was quantified using a magnetic device.
RESULTS: Transient increases in neuronal [Ca2?]i induced by pruritic PBC and ICP sera were higher than corresponding controls. Lysophosphatidic acid (LPA) could be identified as a major [Ca2?]i agonist in pruritic sera, and LPA concentrations were increased in cholestatic patients with pruritus. LPA injected intradermally into mice induced scratch responses. Autotaxin, the serum enzyme converting lysophosphatidylcholine into LPA, was markedly increased in patients with ICP versus pregnant controls (P ?<.0001) and cholestatic patients with versus without pruritus (P <? .0001). Autotaxin activity correlated with intensity of pruritus (P ?<.0001), which was not the case for serum bile salts, histamine, tryptase, substance P, or ?-opioids. In patients with PBC who underwent temporary nasobiliary drainage, both itch intensity and autotaxin activity markedly decreased during drainage and returned to preexistent levels after drain removal.
CONCLUSIONS: We suggest that LPA and autotaxin play a critical role in cholestatic pruritus and may serve as potential targets for future thera- peutic interventions.
Keywords: Autotaxin; Bile Salts; Cholestasis; Itch.

Journal Club 2015.10.16

By Won-Sik Shim

Cell Rep. 2015 Oct 13;13(2):387-98. doi: 10.1016/j.celrep.2015.09.002. Epub 2015 Oct 1.

ASIC3 Mediates Itch Sensation in Response to Coincident Stimulation by Acid and Nonproton Ligand.

Peng Z, Li WG, Huang C, Jiang YM, Wang X, Zhu MX, Cheng X, Xu TL.

Abstract

The regulation and mechanisms underlying itch sensation are complex. Here, we report a role for acid-sensing ion channel 3 (ASIC3) in mediating itch evoked by certain pruritogens during tissue acidosis. Co-administration of acid with Ser-Leu-Ile-Gly-Arg-Leu-NH2 (SL-NH2) increased scratching behavior in wild-type, but not ASIC3-null, mice, implicating the channel in coincident detection of acidosis and pruritogens. Mechanistically, SL-NH2 slowed desensitization of proton-evoked currents by targeting the previously identified nonproton ligand-sensing domain located in the extracellular region of ASIC3 channels in primary sensory neurons. Ablation of the ASIC3 gene reduced dry-skin-induced scratching behavior and pathological changes under conditions with concomitant inflammation. Taken together, our data suggest that ASIC3 mediates itch sensation via coincident detection of acidosis and nonproton ligands that act at the nonproton ligand-sensing domain of the channel.

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Journal Club 2015.10.02.

By onlynice20

Oral supplementation with fish oil reduces dryness and pruritus in the acetone-induced dry skin rat model

1-s2.0-S0923181115300207-main

Raquel C.S. Barcelosa,b,c,d,f, Cristina de Mello-Sampayob,c,f,*, Caren T.D. Antoniazzia, Hecson J. Segata, Henrique Silvad, Juliana C. Veite, Jaqueline Piccoloe,
Tatiana Emanuellia,e, Marilise E. Bürgera, Beatriz Silva- Limab,c, Luis M. Rodriguesb,d
a Universidade Federal de Santa Maria (UFSM), Programa de Pós-Graduação em Farmacologia, Santa Maria, RS, Brazil
b Pharmacological Sciences Department, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal
c Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal
d CBIOS, Research Center for Bioscience and Health Technologies, Universidade Lusófona, Lisboa, Portugal
e Departamento de Tecnologia dos Alimentos, Programa de Pós-Graduação em Ciência Tecnologia dos Alimentos, Universidade Federal de Santa Maria, Av. Roraima, 1000, 97105-900 Santa Maria, RS, Brazil
f Both authors have contributed equally to this work.

Background: Pruritus and discomfort are often present in patients with xerosis and atopic dermatitis. Several studies suggest an important role of diet in skin pathophysiology.
Objective: This study evaluated the effect of dietary fatty acids in the skin physiology via an itch-related animal model with and without supplementation with fish oil (FO), a source of polyunsaturated fatty acids (PUFA), especially omega 3 (n-3).
Methods: Male Wistar rats were divided into two groups—non-supplemented (control) and supplemented with FO (3g/kg/day) by gavage for 90 days. Every 30 days, scratching and skin parameters (transepidermal water loss (TEWL), hydration, and local blood flow) were evaluated before and after dorsal skin exposure to acetone to induce the itch-related dry skin. At the end of the study, animals were sacrificed, and skin samples collected for fatty acids composition analysis by GC–FID. Results: FO supplementation reduced the TEWL and increased the skin hydration, with significant changes from day 60 on, while skin microcirculation registered no changes. It also alleviated the acetone induced skin barrier alteration, revealed by a faster resolution of TEWL and hydration, and elimination of itch-related scratching induced by dry skin. These changes were associated with the shift in the skin fatty acids incorporation pattern (richer in n-3 with n-6/n-3 < 5) resulting from the FO supplementation. Conclusion: Skin barrier dynamics seem to be influenced by FO n-3 PUFA, with suppressive effects on the scratching behaviour induced by dry skin. Hence, long-term supplementation with n-3 PUFA rich nutrients might reinforce and restore cutaneous integrity and function.
ã 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.