Chronic itch development in sensory neurons  requires BRAF signaling pathways.
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.
Zhong-Qiu
ZQ
Zhao
Fu-Quan
FQ
Huo
Joseph
J
Jeffry
Lori
L
Hampton
Shadmehr
S
Demehri
Seungil
S
Kim
Xian-Yu
XY
Liu
Devin M
DM
Barry
Li
L
Wan
Zhong-Chun
ZC
Liu
Hui
H
Li
Ahu
A
Turkoz
Kaijie
K
Ma
Lynn A
LA
Cornelius
Raphael
R
Kopan
James F
JF
Battey
Jian
J
Zhong
Zhou-Feng
ZF
Chen
D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D019886:Gastrin-Releasing Peptide / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000235:genetics / Q000502:physiology; D009619:Nociceptors / Q000502:physiology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000502:physiology*; D011537:Pruritus / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology*; D018004:Receptors, Bombesin / Q000235:genetics / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology; D011984:Sensory Receptor Cells / Q000502:physiology*; D013116:Spinal Cord / Q000503:physiopathology; D050916:TRPV Cation Channels / Q000235:genetics / Q000502:physiology
C546475:MrgprA3 protein, mouse; D062559:NAV1.8 Voltage-Gated Sodium Channel; D018004:Receptors, Bombesin; D043562:Receptors, G-Protein-Coupled; C568318:Scn10a protein, mouse; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D019886:Gastrin-Releasing Peptide; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf