Persistent Extracellular Signal-Regulated Kinase Activation by the Histamine H4 Receptor in Spinal Neurons Underlies Chronic Itch.

Abstract

Transient extracellular signal-regulated kinase (ERK) activation in the spinal cord triggers histamine-induced acute itch. However, whether persistent ERK activation plays an important role in chronic itch development remains unclear. This study investigated the role of spinal ERK activation in chronic itch. The results showed that repetitive DNFB painting on the nape of mice evoked not only initial scratching but also sustained, spontaneous scratching. In addition, DNFB induced itching rather than nociception, as demonstrated using a cheek model. Furthermore, ERK was persistently activated in the spinal cord of DNFB-treated mice, and the intrathecal inhibition of phosphorylation of ERK suppressed both spontaneous itching and ERK activation. ERK activation was observed in neurons but not in glia cells during chronic itch development. Finally, DNFB-induced spontaneous itching behavior and ERK activation were largely inhibited by the histamine H4 receptor antagonist JNJ7777120 but not by the H1 receptor antagonist chlorpheniramine. Our results indicate that persistent ERK activation via the histamine H4 receptor in spinal neurons underlies DNFB-induced chronic itch.

• Authors: Kun Huang, Dan-Dan Hu, Dong Bai, Ze-Yang Wu, Yi-Yang Chen, Yi-Jun Zhang, Xin Lv, Qing-Xiu Wang, Ling Zhang
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 138 Issue 8 Pg. 1843-1850 (08 2018) ISSN: 1523-1747 [Electronic] United States
• PMID: 29486155 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Histamine H1 Antagonists
• Hrh4 protein, mouse
• Indoles
• Piperazines
• Receptors, Histamine H1
• Receptors, Histamine H4
• 1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine
• Dinitrofluorobenzene
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Behavior, Animal (drug effects)
• Chronic Disease
• Dinitrofluorobenzene (toxicity)
• Disease Models, Animal
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Histamine H1 Antagonists (pharmacology)
• Humans
• Indoles (pharmacology)
• MAP Kinase Signaling System (drug effects)
• Male
• Mice
• Mice, Inbred ICR
• Nociception (drug effects)
• Piperazines (pharmacology)
• Pruritus (chemically induced, pathology)
• Receptors, Histamine H1 (metabolism)
• Receptors, Histamine H4 (antagonists & inhibitors, metabolism)
• Sensory Receptor Cells (drug effects, metabolism)
• Skin (innervation)
• Spinal Cord (cytology)