Peripheral and Central Mechanisms of Itch

Abstract

Itch is a unique sensory experience that is encoded by genetically distinguishable neurons both in the peripheral nervous system (PNS) and central nervous system (CNS) to elicit a characteristic behavioral response (scratching). Itch interacts with the other sensory modalities at multiple locations, from its initiation in a particular dermatome to its transmission to the brain where it is finally perceived. In this review, we summarize the current understanding of the molecular and neural mechanisms of itch by starting in the periphery, where itch is initiated, and discussing the circuits involved in itch processing in the CNS.

Keywords: G protein-coupled receptors; TRP channels; cytokines; dorsal root ganglia; itch; mast cells; neuroimmunology; pain; sensory neuron; spinal cord.

Figure 1. Peripheral mediators of itch

The skin is a laminated structure that serves as a protection barrier. When a skin area is irritated or infected, keratinocytes and local immune cells release various mediators to mount an immune response and eradicate the insult. Itch sensory neurons that innervates the dermatome extend free nerve ending in the epidermis and express receptors that, once bound by the ligands, can trigger neuronal firing. Itch mediators with identified neuronal receptors include TSLP and IL-33 most secreted by keratinocytes, mast cell mediators including histamine, serotonin and various proteases, as well as several cytokines associated with T_H2 type T helper cells including IL-4, IL-13 and IL-31.

Figure 2. Neuronal itch receptor activation and downstream signaling

Several known itch mediators bind to G protein coupled receptors (GPCRs) on the neuronal membrane. Each of the GPCRs signal through their coupled G protein pathways but all require the TRP family cation channels. Cytokine receptors, on the other hand, signal through classical Janus kinase and MAP kinase pathways but also require the TRP ion channels to trigger itch neuronal firing.

Figure 3. Hypothetical schematic of peripheral and central itch circuits based on current knowledge

Primary somatosensory neurons in the DRG can be categorized by their gene expression profiles. Single cell expression profiling revealed 3 subtypes of itch neurons termed NP1, NP2 and NP3. NP1 neurons are characterized by their expression of MrgprD, NP2 by MrgprA3 and NP3 by serotonin receptors. The MrgprA3+ NP2 neurons have been shown to be itch specific neurons since activating these neurons elicit only itch behaviors. Itch sensory neurons make synaptic connections with GRP+ interneurons in the spinal cord, which are in turn connected with GRPR+ neurons. Ablation of GRPR signaling or GRPR+ neurons will completely abolish response to itchy stimuli, indicating vital importance of this pathway in itch transmission. Information about itch stimuli in the periphery is eventually conveyed to higher brain centers by projection neurons. The parabrachial nucleus (PBN) in the brainstem serves as an important relay center in the process. Itch interacts with other sensory modalities in the spinal cord. GRP+ neurons receive both itch and pain stimuli but will inhibit their own responses to high intensity pain sensation through enkaphalin signaling. Meanwhile, a painful stimulus will activate both itch and pain sensory neurons. But only pain will be perceived because itch is inhibited by pain via inhibitory interneurons in the spinal cord. One group of these interneurons is marked by the transcription factor BHLHB5. These neurons are activated by a variety of anti-itch stimuli and likely inhibit itch via the release of dynorphin and glycine. Similarly, a group of inhibitory interneurons labeled by the NPY neuropeptide were shown to mediate the inhibition of mechanical itch by light touch, though the sensory neurons and further transduction circuits of mechanical itch remain to be identified. The spinal cord dorsal horn also receives descending neuromodulation from higher brain centers. The raphe magnus (NRM) sends serotoninergic projections to the spinal cord and can stimulate GRPR+ neurons and potentiate itch by co-activating HTR1A and GRPR receptors. The dorsal horn also receives tonic noradrenergic inhibition, likely from the locus coeruleus (LC). GRPR+ neurons in the suprachiasmatic nucleus (SCN) of the hypothalamus have been suggested to play a role in contagious itch.