Central circuit mechanisms of itch

Abstract

Itch, in particular chronic forms, has been widely recognized as an important clinical problem, but much less is known about the mechanisms of itch in comparison with other sensory modalities such as pain. Recently, considerable progress has been made in dissecting the circuit mechanisms of itch at both the spinal and supraspinal levels. Major components of the spinal neural circuit underlying both chemical and mechanical itch have now been identified, along with the circuits relaying ascending transmission and the descending modulation of itch. In this review, we summarize the progress in elucidating the neural circuit mechanism of itch at spinal and supraspinal levels.

Fig. 1. Model of spinal circuits for chemical and mechanical itch.

a When activated by chemical itch stimuli, the peripheral pruriceptors send the itch signals to spinal NPRA⁺ neurons via Nppb, a primary itch transmitter. The secondary sensory (NPRA⁺ or GRP⁺) neurons then activate GRPR⁺ neurons by releasing GRP, after which the itch signals are conveyed to the spinal projection neurons before reaching the thalamus or PBN for further processing. GRP was also proposed as another peripheral itch transmitter in some studies. The chemical itch circuit is gated by spinal inhibitory interneurons marked by Bhlhb5, which also coexpress DYN and Sst2a. These neurons are inhibited by peripheral-derived SST, while in turn inhibiting itch via the release of DYN and GABA/glycine. Spinal galanin⁺ neurons also gate chemical itch processing by directly inhibiting the activity of GRPR⁺ neurons, and the majority of these inhibitory neurons overlap with DYN/Bhlhb5⁺ neurons. b Light touch stimuli activate LTMRs to evoke mechanical itch, and the mechanical itch information is transmitted to spinal Ucn3⁺ neurons, a subset of which also express NPY1R, and these neurons are gated by spinal inhibitory NPY⁺ neurons through NPY-NPY1R signaling as well as the inhibitory neurotransmitters GABA/glycine. PN projection neuron, LTMR low-threshold mechanoreceptor, Glu glutamate.

Fig. 2. Brain circuits for itch signal processing and modulation.

The chemical itch signals are first relayed to the PBN and thalamus by spinal projection neurons, while visually contagious itch in mice is proposed to be mediated by the SCN GRPR⁺ neurons in the hypothalamus. The emotional components of itch sensation may be encoded by the amygdala, GABAergic neurons in the PAG, and different neuronal populations in the VTA. The PAG^Tac1-RVM circuit is involved in the descending modulation of itch signal processing, and brain-derived neuromodulators such as 5-HT and noradrenaline can also substantially modulate spinal itch circuits in a feedback manner. Projections from the ACC to the DMS selectively modulate histamine-dependent itch. AMY amygdala, LC locus coeruleus, NE noradrenaline.