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 November 1, 2013; First 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 6

Generation of Grp–/– mice and confirmation of GRP expression in primary sensory neurons.

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Generation of Grp–/– mice and confirmation of GRP expression in primary ...
(A) Targeting strategy for generation of Grp–/– mice. (B and C) Germ line transmission was confirmed by (B) Southern blot and (C) PCR analysis. (D–G) GRP expression in the (D and E) DRGs and (F and G) spinal cords of (D and F) wild-type mice and (E and G) Grp–/– mice. (H–O) Expression of (H–J) CGRP and (K–O) GRP in the lumbar spinal cords of C57BL/6J mice 14 days after unilateral dorsal rhizotomy (L5). On contralateral sides, both (H and I) CGRP+ and (K, L, and N) GRP+ fibers were mainly in the superficial dorsal horn (lamina I, IIo); but on the ipsilateral sides, both (H and J) CGRP and (K, M, and O) GRP staining was lost after unilateral L5 dorsal rhizotomy. Arrows indicate the elimination of staining. n = 3 per group. (P) Quantitation of remaining CGRP+ (15.1%) and GRP+ (10.2%) staining in the L5 superficial dorsal horn after rhizotomy. Boxed areas in L and M are shown at higher magnification in N and O. Scale bar: 10 μm (D and E); 20 μm (F and G); 40 μm (H–O).