Itch Signaling in the Nervous System

Abstract

Itch is a major somatic sensation, along with pain, temperature and touch, detected and relayed by the somatosensory system. Itch can be an acute sensation, associated with mosquito bite, or a chronic condition, like atopic dermatitis (29, 59). The origins of the stimulus can be localized in the periphery or systemic, and associated with organ failure or cancer. Itch is also a perception originating in the brain. Itch is broadly characterized as either histamine-dependent (histaminergic) or histamine-independent (nonhistaminergic), both of which are relayed by subsets of C-fibers, and by the second-order neurons expressing gastrin-releasing peptide receptor (GRPR) and spinothalamic track (STT) neurons in the spinal cord of rodents. Historically, itch research has been primarily limited to clinical and psychophysical studies, and to histamine-mediated mechanisms. In contrast, little is known about signaling mechanisms underlying nonhistaminergic itch, despite the fact that the majority of chronic itch are mediated by nonhistaminergic mechanisms. During the past few years, important progress has been made in understanding of molecular signaling of itch, largely due to the introduction of mouse genetics. In this review, we examine some of molecular mechanisms underlying itch sensation with an emphasis on recent studies in rodents.

Making sense out of spinal cord somatosensory development

“…Although GRPR + neurons reside in lamina I, they appear to be distinct from STT neurons. Further work is necessary to understand how itch and pain sensations relate (Braz et al, 2014;Jeffry et al, 2011;Ross, 2011), and identifying further subpopulations of the dI5/dIL B lineage should help catalyze this discussion.…”

Chronic itch development in sensory neurons requires BRAF signaling pathways

“…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)(2)(3)(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)(6)(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)(9)(10).…”

TRP Channels and Pruritus

“…However, several other skin diseases (e.g. AD) with chronic pruritus are very often resistant to antihistamine therapies [54,55,60]. In a mouse dry skin model, histamine (in contrast of other itch inductors) did not stimulate scratching behavior [61], further supporting the hypothesis that histamine is not a central mediator of chronic pruritus.…”

“…Histamine is probably the most-known pruritogen [54,55]. It is mostly released from activated mast cells and basophil granulocytes, central players in local cutaneous inflammatory as well as systemic allergic responses [56,57].…”

“…Among them, H 1 and H 4 are widely accepted as receptors responsible for itch sensation; however, quite interestingly, an H 3 receptor inverse agonist was also shown to induce scratching behavior in mice [54,62,63].…”