Chronic itch development in sensory neurons requires BRAF signaling pathways
JCI70528
Zhong-Qiu Zhao,1,2 Fu-Quan Huo,1,2 Joseph Jeffry,1,2 Lori Hampton,3 Shadmehr Demehri,4,5 Seungil Kim,1 Xian-Yu Liu,1,2 Devin M. Barry,1,5 Li Wan,1,6 Zhong-Chun Liu,1,2 Hui Li,1,7 Ahu Turkoz,4 Kaijie Ma,8 Lynn A. Cornelius,1,5 Raphael Kopan,4 James F. Battey Jr.,9
Jian Zhong,8,10 and Zhou-Feng Chen1,2,4
1Center for the Study of Itch and 2Departments of Anesthesiology and Psychiatry, Washington University School of Medicine Pain Center,
St. Louis, Missouri, USA. 3Office of Laboratory Animal Welfare, NIH, Bethesda, Maryland, USA. 4Department of Developmental Biology and 5Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA. 6Department of Anesthesiology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
7Department of Anatomy, Histology, and Embryology and K.K. Leung Brain Research Centre, The Fourth Military Medical University, Xi’an, China. 8Burke Medical Research Institute, Weill Medical College of Cornell University, White Plains, New York, USA.
9National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland, USA.
10Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, New York, USA.
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 excit- ability, 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 main- taining 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.