Molecular dissection of itch

Abstract

There have been many exciting recent advances in our understanding of the molecular and cellular basis of itch. These discoveries cover diverse aspects of itch sensation, from the identification of new receptors to the characterization of spinal cord itch circuits. A common thread of these studies is that they demonstrate that itch sensory signals are segregated from input for other somatosensory modalities, such as pain, touch, and thermosensation. This specificity is achieved by the expression of dedicated receptors and transmitters in a select population of sensory neurons which detect pruritogens. Further, recent studies show that itch specificity is maintained in a spinal cord circuit by the utilization of specific neurotransmitters and cognate receptors to convey input along a distinct cellular pathway.

Figure 1

Model depicting the cellular and molecular components responsible for the peripheral detection of itch stimuli. The skin is a complex micro-environment containing multiple cell-types that collaborate to detect and either directly or indirectly stimulate pruciceptive neurons. Skin and immune cells as well as agents released from invading organisms activate sensors in the itch-responsive nerve fibers in the skin. Through different signaling cascades G protein-coupled receptors (GPCR) and cytokine receptors cause the cells in which they are expressed to be depolarized.

Figure 2

Schematic of the itch spinal cord circuit. The initial stages of the itch-circuit in the spinal cord are characterized by the expression of neuropeptides and the post-synaptic expression of their cognate receptors. Initially Nppb is released from primary puriceptive neurons (black arrow) and activates Npr1-expressing spinal cord neurons. In turn, Npr1-neurons release GRP which activates tertiary GRPR-expressing cells. The GRPR-neurons then directly or indirectly, (broken white arrow) activate projection neurons which send projections to higher brain centers. Inhibitory Bhlhb5-interneurons (green) express Sst2a receptors and can be hyperpolarized by somatostatin. The Bhlhb5-cells are thought to release the kappa-opioid dynorphin in response to activation by primary afferent DRG stimulation. Dynorphin causes inhibition of the excitatory (red) itch pathway.