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

Neuropharmacology. 2020 Jun 15:170:108025. doi: 10.1016/j.neuropharm.2020.108025. Epub 2020 Mar 3.

Abstract

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.

Keywords: Chloroquine; Glutamate; Histamine; Nonhuman primate; Pain; Pruritus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bombesin / analogs & derivatives
  • Bombesin / pharmacology
  • Cyclopropanes / toxicity
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Antagonists / pharmacology
  • Macaca mulatta
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Neurons / drug effects
  • Neurons / metabolism*
  • Peptide Fragments / pharmacology
  • Pruritus / chemically induced
  • Pruritus / metabolism*
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, AMPA / metabolism*
  • Receptors, Bombesin / antagonists & inhibitors
  • Receptors, Bombesin / metabolism*
  • Spinal Cord Dorsal Horn / drug effects
  • Spinal Cord Dorsal Horn / metabolism*

Substances

  • Cyclopropanes
  • Excitatory Amino Acid Antagonists
  • Peptide Fragments
  • Receptors, AMPA
  • Receptors, Bombesin
  • bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-
  • diphenylcyclopropenone
  • Bombesin