Intrinsic braking role of descending locus coeruleus noradrenergic neurons in acute and chronic itch in mice
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RESEARCH
Intrinsic braking role of descending locus coeruleus noradrenergic neurons in acute and chronic itch in mice Keisuke Koga1,2, Yuto Shiraishi1,3, Ryo Yamagata1, Hidetoshi Tozaki‑Saitoh1,3, Miho Shiratori‑Hayashi1,3 and Makoto Tsuda1,3*
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 poten‑ tial 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 CRISPRCas9 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. Keywords: Descending noradrenaline neurons, Locus coeruleus, Spinal dorsal horn, Gastrin-releasing peptide receptor-expressing neurons, Itch, Mouse Introduction Itch is defined as an unpleasant cutaneous sensation that provokes the desire to scratch, and scratching can transiently relieve such itching sensations [1]. However, in pathological conditions such as atopic and contact dermatitis, itch sensation becomes intense and chronic, which leads to excessive, repetitive scratching. As the existing treatments (e.g., antihistamines) are largely *Correspondence: [email protected]‑u.ac.jp 3 Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3‑1‑1 Maidashi, Higashi‑ku, Fukuoka 812‑8582, Japan Full list of author information is available at the end of the article
ineffective, the elucidation of the mechanisms underlying chronic itch and the development of novel therapeutic agents are crucial. Pruriceptive information is conveyed via primary afferents from the skin and processed in the spinal dorsal horn (SDH). Recent studies have progressively advanced our understanding of the mechanism underlying neuronal circuits
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