Advances in Understanding the Initial Steps of Pruritoceptive Itch: How the Itch Hits the Switch

Abstract

Pruritoceptive (dermal) itch was long considered an accompanying symptom of diseases, a side effect of drug applications, or a temporary sensation induced by invading pruritogens, as produced by the stinging nettle. Due to extensive research in recent years, it was possible to provide detailed insights into the mechanism of itch mediation and modulation. Hence, it became apparent that pruritus is a complex symptom or disease in itself, which requires particular attention to improve patients' health. Here, we summarize recent findings in pruritoceptive itch, including how this sensation is triggered and modulated by diverse endogenous and exogenous pruritogens and their receptors. A differentiation between mediating pruritogen and modulating pruritogen seems to be of great advantage to understand and decipher the molecular mechanism of itch perception. Only a comprehensive view on itch sensation will provide a solid basis for targeting this long-neglected adverse sensation accompanying numerous diseases and many drug side effects. Finally, we identify critical aspects of itch perception that require future investigation.

Keywords: GPCR; dermal itch; histamine; interleukin; itch; mediator; modulator; non-histaminergic; pruritus; receptors.

Figure 1

Pathway of itch. Itch sensation is caused by exogenous (green) and endogenous (cyan) pruritogens, that bind to itch receptors in free nerve endings of C fibers within the epidermis (yellow) and Aδ fibers within the dermis (grey). In addition, endogenous pruritogens (cyan) can be produced by epidermal keratinocytes and dermal immune cells (purple). The triggered signal is transmitted through peripheral afferent nerve fibers (yellow and grey) of the peripheral nervous system to the central nervous system (CNS), eventually resulting in itch sensation. (Figure adapted from [28]).

Figure 2

Two main types of itch receptors. Itch receptors can be grouped in two main types, interleukins and G protein-coupled receptor (GPCRs). Toll-like receptors (TLRs) and interleukin receptors (ILRs) are part of the Interleukin-1 Receptor/Toll-like Receptor Superfamily. GPCRs are divided into three sub-types, classic GPCRs, protease activated receptors that dimerize [41,42], and GPCRs which require a receptor activity modifying protein (CGRP).

Figure 3

Schematic representation of the 13 major receptor groups involved in itch and their endogenous pruritogens. Each receptor is colored based on two parameters: First, GPCR signaling (blue button) or non-GPCR signaling (white button) and second, ion channel signaling pathway. TRPA1/TRPV1 signaling is represented by a blue sector, TRPV1 signaling is represented by a yellow sector and TRPA1 signaling is represented by an orange sector. The arrows indicate the type of contribution of the receptor and its endogenous pruritogens to itch sensation. White arrows represent itch modulators and grey arrows represent itch mediators.