Scratching the itch


Chronic itchiness is a symptom of many different skin diseases. The development of the itch sensation is triggered by sensory neurons and this signal is then transferred to the brain. G-coupled protein receptor (GPCR) pathways are thought to convey the itch signal and dysregulation of these pathways promotes chronic itch development. Zhong-Qiu Zhao and colleagues at Washington University developed a mouse model of chronic itch, in which a constitutively active form of the serine-threonine kinase BRAF was expressed in sensory neurons (BRAFNav1.8 mice). Compared to wild-type mice, these mice exhibited more spontaneous itch behavior and developed an enhanced scratching response to pruritogens. The authors found that BRAFNav1.8 mice had enhanced expression of the gene encoding the itch-sensing gastrin-releasing peptide receptor (GRPR), which sustained activation of ERK in neurons and the itch sensation. Pharmacological inhibition of BRAF and subsequent GRPR signaling attenuated itch sensation in the chronic itch mouse model. The above image illustrates the increase of pERK+ cells as indicated by double staining with pERK (red) and IB4 (green) in dorsal root ganglia from a BRAFNav1.8 mouse.  

Published October 15, 2013, by Corinne Williams

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Chronic itch development in sensory neurons requires BRAF signaling pathways
Zhong-Qiu Zhao, … , Jian Zhong, Zhou-Feng Chen
Zhong-Qiu Zhao, … , Jian Zhong, Zhou-Feng Chen
Published October 15, 2013
Citation Information: J Clin Invest. 2013;123(11):4769-4780. https://doi.org/10.1172/JCI70528.
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Research Article Dermatology

Chronic itch development in sensory neurons requires BRAF signaling pathways

Abstract

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 excitability, 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 maintaining 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.

Authors

Zhong-Qiu Zhao, Fu-Quan Huo, Joseph Jeffry, Lori Hampton, Shadmehr Demehri, Seungil Kim, Xian-Yu Liu, Devin M. Barry, Li Wan, Zhong-Chun Liu, Hui Li, Ahu Turkoz, Kaijie Ma, Lynn A. Cornelius, Raphael Kopan, James F. Battey Jr., Jian Zhong, Zhou-Feng Chen

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