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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Figure 1

Increased levels of pMEK1/2 and pERK1/2 in sensory neurons and aberrant innervations in the spinal cords of BRAFNav1.8 mice.

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Increased levels of pMEK1/2 and pERK1/2 in sensory neurons and aberrant ...
(A) A representative Western blot and (B) quantified data show increased levels of pMEK1/2 and pERK1/2 but unchanged total MEK1/2 and ERK1/2 levels in DRGs of BRAFNav1.8 mice. n = 6 per genotype. All the lanes were run on the same gel but are noncontiguous. *P < 0.05, **P < 0.01, BRAFNav1.8 mice vs. wild-type. (C–F) Increased pERK+ cells are indicated by double staining with pERK (red) and IB4 (green) or with pERK (brown) in Trpv1+ (blue) cells in BRAFNav1.8 mice compared to wild-type mice. n = 4 per genotype. ***P < 0.001. (G–L) Expression of molecular markers with IB4 (green) in DRGs of wild-type and BRAFNav1.8 mice. (M) Quantitative comparison of DRG neurons between 2 groups. n = 3 per genotype. (N–P) Expression of (N) CGRP and (O) IB4 in the spinal cords of wild-type and BRAFNav1.8 mice. Arrows and arrowheads indicate (C and E) pERK+ or pERK– cells, respectively, and (G–L) IB4+ or IB4– cells, respectively. Scale bar: 20 μm.