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 (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. IntroductionThe 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

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Importantly, loss of vesicular glutamate transporter-2 renders mice less sensitive to pain but, paradoxically, more sensitive to itch (Lagerström et al, 2010;Liu et al, 2010b). Mice that express a constitutively active form of the serine/threonine kinase BRAF (member B of the Raf-kinase family of growth signal transduction proteins kinases) in their sensory neurons gated by Na v 1.8 (so-called BRAFNa v 1.8 mice) show spontaneous scratching behavior indicative of chronic pruritus (Zhao et al, 2013b). A subset of TRPV1 + neurons contains the neuropeptide natriuretic polypeptide b (Nppb).…”

Mas and Its Related G Protein–Coupled Receptors, Mrgprs

“…When the expression of TRPV1, which is involved in itch and thermosensation , was only rescued in mMrgprA3-expressing neurons of a TRPV1 knockout mouse, these animals reacted only with itch response on intradermal injections of capsaicin, which in normal animals would also induce pain . Concordantly, the overexpression of mMrgprA3 in TRPV1-positive nociceptors induced by a BRAF-expressing transgene led to a marked increase in their response to pruritogens (Zhao et al, 2013). Nevertheless, the main channel activated by mMrgprA3 during pruriception is not TRPV1 but transient receptor potential ankyrin 1 (TRPA1), because TRPA1 knockout mice hardly respond to the mMrgprA3 agonist chloroquine (Wilson et al, 2011), whereas in TRPV1 knockout mice only histamine-induced itch is blunted (Imamachi et al, 2009).…”

Inhibition of the mammalian target of rapamycin complex 1 signaling pathway reduces itch behaviour in mice

“…12 Also, gastrin-releasing peptide (GRP)-expressing primary afferents have also been proposed to play a role in itch sensation. 42,45 Our previous work identified 1 group of small-diameter Adnociceptors as containing an activated form of the mammalian target of rapamycin (mTOR), a kinase that maintains the excitability of these A-fibers. 9,18,31 mTOR belongs to the phosphatidylinositol 3-kinase-related kinase protein family and forms at least 2 multiprotein complexes known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).…”