Intrinsic braking role of descending locus coeruleus noradrenergic neurons in acute and chronic itch in mice

Keisuke Koga,Ryo Yamagata,Yuto Shiraishi,Hidetoshi Tozaki-Saitoh,Miho Shiratori-Hayashi,Makoto Tsuda

doi:10.1186/s13041-020-00688-0

Abstract

Itch is defined as an unpleasant sensation that provokes a desire to scratch. Our understanding of neuronal circuits for itch information transmission and processing in the spinal dorsal horn (SDH) has progressively advanced following the identification of SDH neuron subsets that are crucial for scratching behavior in models of itch. However, little is known about the control of acute and chronic itch by descending signals from the brain to the SDH. In this study, using genetic approaches that enable cell-type and circuit-specific functional manipulation, we reveal an intrinsic potential of locus coeruleus (LC)-noradrenergic (NAergic) neurons that project to the SDH to control acute and chronic itch. Activation and silencing of SDH-projecting LC-NAergic neurons reduced and enhanced scratching behavior, respectively, in models of histamine-dependent and -independent acute itch. Furthermore, in a model of chronic itch associated with contact dermatitis, repetitive scratching behavior was suppressed by the activation of the descending LC-NAergic pathway and by knocking out NA transporters specific to descending LC-NAergic neurons using a CRISPR-Cas9 system. Moreover, patch-clamp recording using spinal slices showed that noradrenaline facilitated inhibitory synaptic inputs onto gastrin-releasing peptide receptor-expressing SDH neurons, a neuronal subset known to be essential for itch transmission. Our findings suggest that descending LC-NAergic signaling intrinsically controls acute and chronic itch and provide potential therapeutic strategies for the treatment of acute and chronic itch.

Highlights

Itch is defined as an unpleasant cutaneous sensation that provokes the desire to scratch, and scratching can transiently relieve such itching sensations [1]
Chemogenetic manipulation of descending locus coeruleus (LC)‐NAergic neurons To investigate the role of descending LC-NAergic neurons, we manipulated the activity of these neurons using chemogenetics [16]
By using genetic approaches that enable cell-type and circuit-specific functional manipulation, we demonstrate for the first time that spinal dorsal horn (SDH)-projecting LCNAergic neurons powerfully control itch-related behavior

Summary

Introduction

Itch is defined as an unpleasant cutaneous sensation that provokes the desire to scratch, and scratching can transiently relieve such itching sensations [1]. Gastrin-releasing peptide receptor (GRPR)-expressing (GRPR+) neurons in the SDH act as a hub for converging pruriceptive information and are essential for producing scratching behaviors in diverse models of acute and chronic itch [6,7,8]. Activation of 5-HT1A receptors potentiates the excitation of G RPR+ neurons via the enhancement of gastrinreleasing peptide (GRP)-induced responses This suggests that the activation of descending 5-HTergic pathways facilitates itch transmission via GRPR signaling in the SDH [9]. While intrathecal treatment with 6-hydroxydopamine (6-OHDA), a neurotoxin that can cause the degeneration of catecholaminergic neurons, has been reported to exacerbate scratching behavior [10], there is no direct evidence for the role of SDH-projecting LC-NAergic neurons in controlling acute and chronic itch

Methods

Results

Conclusion