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 4

Enhanced and de novo responses to CQ and histamine but not to capsaicin in DRG cells from BRAFNav1.8 mice.

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Enhanced and de novo responses to CQ and histamine but not to capsaicin ...
(A and B) Three representative traces of DRG cells from (A) wild-type or (B) BRAFNav1.8 mice responsive to CQ (100 μM), histamine (50 μM), and capsaicin (Cap; 1 μM). (B) Note that one CQ-responsive cell tested also responded to histamine and capsaicin. (C) The percentage of CQ-responsive DRG cells, but not histamine- and capsaicin-responsive cells, was significantly increased in BRAFNav1.8 mice. More DRG cells responded to both CQ and histamine in BRAFNav1.8 mice than in wild-type mice. (D) Of all capsaicin-sensitive cells in BRAFNav1.8 mice, there was a significant increase of cells that responded to CQ or to both CQ and histamine, whereas no difference was detected in the percentage of cells responsive to both capsaicin and histamine. (E and F) Venn diagrams showing the relative proportions of DRG cells of (E) wild-type mice and (F) BRAFNav1.8 mice responsive to CQ, histamine, and capsaicin. *P < 0.05, **P < 0.01, BRAFNav1.8 vs. wild-type. n = 4 (a total of 1,161 cells were tested).