Itch: Cells, Molecules, and Circuits

Abstract

The itch field has made great advances in recent years, building upon earlier work to form a clearer picture of the biology behind this important sensory modality. Models for how itch is encoded have emerged that fit with physiological, molecular, and behavioral data. The molecular mechanisms of itch, both peripherally and centrally, are being revealed with the aid of newer animal models. Future work must address shortcomings in our current understanding of itch including limitations of current experimental methods. Here we review what is known about the cells, molecules, and circuits involved in itch and highlight key questions that remain to be answered.

Figure 1

Itch coding models. (A) Intensity theory hypothesizes individual neurons that signal either itch or pain through lower or higher intensity stimuli (represented by low and high frequency spiking), respectively. (B) Labeled line theory hypothesizes entirely separate neurons and circuitry for detecting pain versus itch. (C) Occlusion theory hypothesizes dual itch/pain-sensing neurons that signal itch when they are selectively activated. Noxious stimuli will activate both this and the pain-only population, leading to inhibition of the itch circuit.

Figure 2

Comparison of signal transduction pathways for itch. (A) Histamine (his) is a ligand for H1R that activates TRPV1 via phoszpholipase intermediaries PLCβ3 and PLA₂. (B) Chloroquine (CQ) activates MrgprA3 leading to TRP channel opening, but the intermediate steps in the pathway are unknown. In the case of both pruritogens, TRPs permit Ca²⁺ influx, which may also have a signaling role.