Why we scratch an itch: the molecules, cells and circuits of itch

Abstract

Itch is described as an irritating sensation that triggers a desire to scratch. However, this definition hardly seems fitting for the millions of people who suffer from intractable itch. Indeed, the Buddhist philosopher Nāgārjuna more aptly stated, "There is pleasure when an itch is scratched. But to be without an itch is more pleasurable still." Chronic itch is widespread and very difficult to treat. In this review we focus on the molecules, cells and circuits in the peripheral and central nervous systems that drive acute and chronic itch transmission. Understanding the itch circuitry is critical to developing new therapies for this intractable disease.

Figure 1

Schematic depicting the cell types involved in the detection of diverse itch stimuli. DRG neurons (blue; left) innervate the skin and can be activated directly by exogenous or endogenous itch-inducing agents (pruritogens) released by keratinocytes, immune cells or neighboring neuronal afferent endings. However, many of these endogenous compounds also activate keratinocytes and various immune cells. In addition, cross-talk between all three cell types, via release of secreted compounds (for example, via neurogenic inflammation), can further modulate cellular responsiveness and itch pathway output. Distinct subsets of sensory neuron afferents innervate the skin and mediate itch signaling (right). The pruritogen histamine activates neurons via the histamine receptor 1 (H1) that leads to the opening of TRPV1 ion channels (red; top right). The pruritogens BAM8–22 and chloroquine activate neurons via MrgprC11 and MgprA3, respectively, leading to opening of TRPA1 channels (red; middle right). The cytokine TSLP activates neurons via TSLPR, which leads to the opening of TRPA1 channels (red; bottom right). The activation of TRPV1 or TRPA1 leads to neuronal depolarization, action potential firing and the transmission of itch signals from the periphery to the CNS. See Table 1 for a complete list of pruritogens and receptors implicated in itch.

Figure 2

Models of peripheral and spinal itch circuitry. (a) Excitatory itch pathways. Sensory neurons have cell bodies in the DRG (blue) and project primary afferents to the skin, where a variety of transduction molecules reside and detect itch, touch and pain stimuli. These neurons also send projections to the dorsal horn of the spinal cord, where they synapse with secondary neurons (gray). Second-order spinal neurons connect with other dorsal horn interneurons and/or spinal thalamic projection neurons (green). Model 1 proposes that GRP is a peripheral itch transmitter that activates GRPR on secondary pruriceptors. Chloroquine, SLIGRL and the mast-cell degranulating compound 48/80 (48/80) all require functional GRP signaling to evoke itch. Histamine (Hist), 5-hydroxytryptamine (5-HT) and endothelin-1 induce itch independent of GRP signaling. Model 2 proposes that BNP serves as a peripheral itch transmitter that activates secondary pruriceptors that express NPRA and GRP. These neurons then activate tertiary GRPR-expressing pruriceptors. Model 3 is a combination of models 1 and 2, in which BNP and GRP act in parallel as peripheral itch transmitters. GRP can be released by DRG neurons and NPRA-positive spinal neurons. BNP activates NPRA-expressing spinal interneurons, and GRP activates GRPR-expressing spinal interneurons. (b) Model for the inhibitory inputs of the itch pathway whereby tonic activity is inhibited by paired activation of the pain circuitry. A subset of VGLUT2-expressing nociceptors in the DRG and a subset of dorsal horn inhibitory interneurons expressing Bhlhb5 specifically suppress itch signal transmission. Connections that are unknown or controversial are shown as dashed magenta arrows. CQ, chloroquine.