GRP receptor and AMPA receptor cooperatively regulate itch-responsive neurons in the spinal dorsal horn

Norikazu Kiguchi*, Daisuke Uta, Huiping Ding, Hitoshi Uchida, Fumihiro Saika, Shinsuke Matsuzaki, Yohji Fukazawa, Manabu Abe, Kenji Sakimura, Mei Chuan Ko, Shiroh Kishioka

*この論文の責任著者

研究成果: ジャーナルへの寄稿学術論文査読

31 被引用数 (Scopus)

抄録

Gastrin-releasing peptide (GRP) receptor-expressing (GRPR)+ neurons have a central role in the spinal transmission of itch. Because their fundamental regulatory mechanisms are not yet understood, it is important to determine how such neurons are excited and integrate itch sensation. In this study, we investigated the mechanisms for the activation of itch-responsive GRPR+ neurons in the spinal dorsal horn (SDH). GRPR+ neurons expressed the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) containing the GluR2 subunit. In mice, peripherally elicited histaminergic and non-histaminergic itch was prevented by intrathecal (i.t.) administration of the AMPAR antagonist NBQX, which was consistent with the fact that firing of GRPR+ neurons in SDH under histaminergic and non-histaminergic itch was completely blocked by NBQX, but not by the GRPR antagonist RC-3095. Because GRP+ neurons in SDH contain glutamate, we investigated the role of GRP+ (GRP+/Glu+) neurons in regulating itch. Chemogenetic inhibition of GRP+ neurons suppressed both histaminergic and non-histaminergic itch without affecting the mechanical pain threshold. In nonhuman primates, i.t. administration of NBQX also attenuated peripherally elicited itch without affecting the thermal pain threshold. In a mouse model of diphenylcyclopropenone (DCP)-induced contact dermatitis, GRP, GRPR, and AMPAR subunits were upregulated in SDH. DCP-induced itch was prevented by either silencing GRP+ neurons or ablation of GRPR+ neurons. Altogether, these findings demonstrate that GRP and glutamate cooperatively regulate GRPR+ AMPAR+ neurons in SDH, mediating itch sensation. GRP–GRPR and the glutamate–AMPAR system may play pivotal roles in the spinal transmission of itch in rodents and nonhuman primates.

本文言語英語
論文番号108025
ジャーナルNeuropharmacology
170
DOI
出版ステータス出版済み - 2020/06/15

ASJC Scopus 主題領域

  • 薬理学
  • 細胞および分子神経科学

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