Chronic Itch Development in Sensory Neurons Requires BRAF Signaling Pathways

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2013 Nov 13

PMID 24216512

Citations 63

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

Affiliations

Soon will be listed here.

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 (BRAF(Nav1.8) mice). We found that constitutive BRAF pathway activation in BRAF(Nav1.8) 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). BRAF(Nav1.8) 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.

Citing Articles

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A thalamic nucleus reuniens-lateral septum-lateral hypothalamus circuit for comorbid anxiety-like behaviors in chronic itch.

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Mechanical and chemical itch regulated by neuropeptide Y-Y signaling.

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