Chronic itch development in sensory neurons requires BRAF signaling pathways

Zhao ZQ, Huo FQ, Jeffry J, Hampton L, Demehri S, Kim S, Liu XY, Barry DM, Wan L, Liu ZC, Turkoz A, Ma K, Cornelius LA, Kopan R, Battey JF, Zhong J, Chen ZF; The Journal of Clinical Investigation vol. 123 (11), November 2013, published online Oct.15, 2013. Read More


The ability of the brain to discriminate pain from itch in order to make binary decisions — eliciting either withdrawal or scratching behavior — is critically dependent on the functional connectivity of the somatosensory system. Itch information, along with pain, is conveyed by primary afferents of the dorsal root ganglion (DRG) to the spinal cord and of the trigeminal ganglion neurons to the trigeminal subnucleus caudalis of the brainstem, respectively, which in turn supplies input to the somatosensory cortex through spinothalamic tract or trigeminothalamic tract neurons (1–4). At the molecular level, emerging evidence suggests that activation of GPCRs in sensory neurons is likely responsible for relaying distinct types of acute stimulus-evoked itch (5–7). In addition, several transient receptor potential (TRP) channels, including TRP vanilloid 1 (TRPV1) and TRPA1, have been implicated in mediating histaminergic and nonhistaminergic itch, respectively (8–10). In the spinal cord, gastrin-releasing peptide (GRP) receptor (GRPR) and neurons expressing GRPR are key mediators dedicated to the coding of itch sensation (11–13). In contrast to acute itch, chronic itch may arise from an altered or diseased state of the skin or immune or nervous systems or from a dysregulation of metabolism. Chronic itch represents a significant clinical problem, largely due to its resistance to most commonly used antihistamine-based therapies (14, 15). To date, little is known about signaling mechanisms underlying chronic itch in the nervous system. At the cellular level, mice lacking the transcription factor Bhlhb5 in a subset of spinal cord cells showed a heightened itch transmission, presumably resulting from a loss of inhibitory interneurons expressing Bhlhb5 during development (16). In contrast, mice lacking spinal GRPR+ neurons lack the ability to sense chronic itch (13). In sensory neurons, the conditional deletion of vesicular glutamate transporter 2 (Vglut2) results in spontaneous itch sensation (17, 18), and TRPA1 is important for dry skin itch (19). Ablation of neurons expressing MAS-related GPCR member A3 (MRGPRA) attenuates dry skin and allergic itch, suggesting that MRGPRA3+ neurons are also important for the development of chronic itch (20). Although GRPR has emerged as an important receptor for mediating acute itch, the function of GRPR and its cognate ligand GRP in chronic itch has not been characterized.
BRAF is a serine/threonine kinase that activates ERK, a member of the MAPKs superfamily, through the RAF/MEK/ERK cascade. Upon activation, pERK triggers the expression of a plethora of transcription factors in the nucleus to regulate a wide array of cellular functions (21, 22). Our previous studies of conditional BRAF loss-of-function mice have uncovered an essential role for RAF signaling in the extension of peripheral sensory projections as well as in the initial development of some of the DRG’s molecular makeup and central projections (23). To further explore potential roles of BRAF signaling in sensory transduction, we generated BRAFNav1.8 mice in which the BRAF kinase is selectively activated in sensory neurons expressing the sodium channel Nav1.8 by genetically replacing the wild-type Braf gene with a kinase-activated one in these neurons (24, 25). BRAFNav1.8 mice exhibited spontaneous scratching behavior, prompting us to hypothesize that BRAF signaling plays a role in pruriceptive transmission.

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Posted on October 21, 2013
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