Journal club 2013-11-29

Chronic itch development in sensory neurons requires BRAF signaling pathways

JCI70528

Zhong-Qiu Zhao,1,2 Fu-Quan Huo,1,2 Joseph Jeffry,1,2 Lori Hampton,3 Shadmehr Demehri,4,5 Seungil Kim,1 Xian-Yu Liu,1,2 Devin M. Barry,1,5 Li Wan,1,6 Zhong-Chun Liu,1,2 Hui Li,1,7 Ahu Turkoz,4 Kaijie Ma,8 Lynn A. Cornelius,1,5 Raphael Kopan,4 James F. Battey Jr.,9
Jian Zhong,8,10 and Zhou-Feng Chen1,2,4

1Center for the Study of Itch and 2Departments of Anesthesiology and Psychiatry, Washington University School of Medicine Pain Center,
St. Louis, Missouri, USA. 3Office of Laboratory Animal Welfare, NIH, Bethesda, Maryland, USA. 4Department of Developmental Biology and 5Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA. 6Department of Anesthesiology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
7Department of Anatomy, Histology, and Embryology and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi’an, China. 8Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, New York, USA.
9National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland, USA.
10Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, New York, USA.

Chronic itch, or pruritus, is associated with a wide range of skin abnormalities. The mechanisms responsible for chronic itch induction and persistence remain unclear. We developed a mouse model in which a constitutively active form of the serine/threonine kinase BRAF was expressed in neurons gated by the sodium channel Nav1.8 (BRAFNav1.8 mice). We found that constitutive BRAF pathway activation in BRAFNav1.8 mice results in ectopic and enhanced expression of a cohort of itch-sensing genes, including gastrin-releasing peptide (GRP) and MAS-related GPCR member A3 (MRGPRA3), in nociceptors expressing transient receptor potential vanilloid 1 (TRPV1). BRAFNav1.8 mice showed de novo neuronal responsiveness to pruritogens, enhanced pruriceptor excit- ability, and heightened evoked and spontaneous scratching behavior. GRP receptor expression was increased in the spinal cord, indicating augmented coding capacity for itch subsequent to amplified pruriceptive inputs. Enhanced GRP expression and sustained ERK phosphorylation were observed in sensory neurons of mice with allergic contact dermatitis– or dry skin–elicited itch; however, spinal ERK activation was not required for main- taining central sensitization of itch. Inhibition of either BRAF or GRP signaling attenuated itch sensation in chronic itch mouse models. These data uncover RAF/MEK/ERK signaling as a key regulator that confers a subset of nociceptors with pruriceptive properties to initiate and maintain long-lasting itch sensation.

Journal club 2013-11-22

1-s2.0-S0014299912003585-main
Filename : 1-s2-0-s0014299912003585-main.pdf (401 KB)
Caption :

Eur J Pharmacol. 2012 Jul 5;686(1-3):16-21. doi: 10.1016/j.ejphar.2012.04.024. Epub 2012 Apr 21.

Cathepsin E induces itch-related response through the production of endothelin-1 in mice.

Source

Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, Japan.

Abstract

This study investigated the pruritogenic potency of cathepsin E, an aspartic protease, and its mechanisms in mice. An intradermal injection of cathepsin E to the rostral back elicited scratching, an itch-associated response, of the injection site. This action was inhibited by the aspartic protease inhibitor pepstatin A, the endothelin ET(A) receptor antagonist BQ-123, and the opioid receptor antagonists naltrexone and naloxone, but not by the H(1) histamine receptor antagonist terfenadine, the proteinase-activated receptor-2 antagonist FSLLRY-NH(2), or mast cell deficiency. Pepstatin A inhibited scratching induced by intradermal injection of the mast-cell degranulator compound 48/80, but not by tryptase, a mast-cell mediator. An intradermal injection of cathepsin E increased endothelin-1 levels in the skin at the injection site. Preproendothelin-1 mRNA was present in primary cultures of keratinocytes, and immunohistochemistry using an antibody recognizing endothelin-1 and big-endothelin-1 revealed immunoreactivity in the epidermis, especially in the prickle and granular cell layers, but not in the basal cell layer. These results suggest that cathepsin E is an endogenous itch inducer, and that its action is mediated at least in part by the production of endothelin-1 in the epidermis.

Copyright © 2012 Elsevier B.V. All rights reserved.

PMID:

 

22546226

 

[PubMed – indexed for MEDLINE]

journal 2013-11-15

all2854

The antagonism of histamine H1 and H4 receptors ameliorates chronic allergic dermatitis via anti-pruritic and anti-inflammatory effects in NC/Nga mice.

Source

Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. yuusuke_oosawa@pharm.kissei.co.jp

Abstract

BACKGROUND:

Although histamine H1 receptor (H1R) antagonists are commonly used to treat atopic dermatitis, the treatment is not always effective. The histamine H4 receptor (H4R) was recently described as important to the pruritus in dermatitis. Here, we investigated whether the combination of a H1R antagonist plus a H4R antagonist attenuates chronic dermatitis in NC/Nga mice.

METHODS:

Chronic dermatitis was developed by repeated challenges with picryl chloride on the dorsal back and ear lobes. The therapeutic effects of the H1R antagonist olopatadine and H4R antagonist JNJ7777120 on scratching and the severity of dermatitis were evaluated. In addition, the mechanisms responsible for the anti-allergic effects of H1R and/or H4R antagonism were examined using bone marrow-derived mast cells (BMMC) and keratinocytes.

RESULTS:

JNJ7777120 attenuated scratching behavior after a single administration and improved dermatitis, as assessed with clinical scores, pathology, and cytokine levels in skin lesions when administered repeatedly. These effects were augmented by combined treatment with olopatadine, having a similar therapeutic efficacy to prednisolone. JNJ7777120 inhibited dose-dependently the production of thymus and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 from antigen-stimulated BMMC. In addition, olopatadine reversed the histamine-induced reduction of semaphorin 3A mRNA in keratinocytes.

CONCLUSION:

Combined treatment with H1R and H4R antagonists may have a significant therapeutic effect on chronic dermatitis through the synergistic inhibition of pruritus and skin inflammation.

© 2012 John Wiley & Sons A/S.

Journal club 2013-11-15

all2854
Filename : all2854.pdf (808 KB)
Caption :

Allergy. 2012 Aug;67(8):1014-22. doi: 10.1111/j.1398-9995.2012.02854.x. Epub 2012 Jun 12.

The antagonism of histamine H1 and H4 receptors ameliorates chronic allergic dermatitis via anti-pruritic and anti-inflammatory effects in NC/Nga mice.

Source

Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. yuusuke_oosawa@pharm.kissei.co.jp

Abstract

BACKGROUND:

Although histamine H1 receptor (H1R) antagonists are commonly used to treat atopic dermatitis, the treatment is not always effective. The histamine H4 receptor (H4R) was recently described as important to the pruritus in dermatitis. Here, we investigated whether the combination of a H1R antagonist plus a H4R antagonist attenuates chronic dermatitis in NC/Nga mice.

METHODS:

Chronic dermatitis was developed by repeated challenges with picryl chloride on the dorsal back and ear lobes. The therapeutic effects of the H1R antagonist olopatadine and H4R antagonist JNJ7777120 on scratching and the severity of dermatitis were evaluated. In addition, the mechanisms responsible for the anti-allergic effects of H1R and/or H4R antagonism were examined using bone marrow-derived mast cells (BMMC) and keratinocytes.

RESULTS:

JNJ7777120 attenuated scratching behavior after a single administration and improved dermatitis, as assessed with clinical scores, pathology, and cytokine levels in skin lesions when administered repeatedly. These effects were augmented by combined treatment with olopatadine, having a similar therapeutic efficacy to prednisolone. JNJ7777120 inhibited dose-dependently the production of thymus and activation-regulated chemokine/CCL17 and macrophage-derived chemokine/CCL22 from antigen-stimulated BMMC. In addition, olopatadine reversed the histamine-induced reduction of semaphorin 3A mRNA in keratinocytes.

CONCLUSION:

Combined treatment with H1R and H4R antagonists may have a significant therapeutic effect on chronic dermatitis through the synergistic inhibition of pruritus and skin inflammation.

© 2012 John Wiley & Sons A/S.

PMID:

 

22686688

 

[PubMed – indexed for MEDLINE]

Journal club 2013-11-01

The Star-Nosed Mole Reveals Clues to the Molecular Basis of Mammalian Touch

Abstract

Little is known about the molecular mechanisms underlying mammalian touch transduction. To identify novel candidate transducers, we examined the molecular and cellular basis of touch in one of the most sensitive tactile organs in the animal kingdom, the star of the star-nosed mole. Our findings demonstrate that the trigeminal ganglia innervating the star are enriched in tactile-sensitive neurons, resulting in a higher proportion of light touch fibers and lower proportion of nociceptors compared to the dorsal root ganglia innervating the rest of the body. We exploit this difference using transcriptome analysis of the star-nosed mole sensory ganglia to identify novel candidate mammalian touch and pain transducers. The most enriched candidates are also expressed in mouse somatosesensory ganglia, suggesting they may mediate transduction in diverse species and are not unique to moles. These findings highlight the utility of examining diverse and specialized species to address fundamental questions in mammalian biology.

Citation: Gerhold KA, Pellegrino M, Tsunozaki M, Morita T, Leitch DB, et al. (2013) The Star-Nosed Mole Reveals Clues to the Molecular Basis of Mammalian Touch. PLoS ONE 8(1): e55001. doi:10.1371/journal.pone.0055001

Editor: Michael N. Nitabach, Yale School of Medicine, United States of America

Received: October 10, 2012; Accepted: December 21, 2012; Published: January 30, 2013

Copyright: © 2013 Gerhold et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The authors are supported by a U.S. National Institutes of Health Innovator Award DOD007123A, the Pew Scholars Program, and the McKnight Scholars Fund (to DMB) and NSF grant 0844743 (to KCC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
journal.pone.0055001

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