Roles of glutamate, substance P, and gastrin-releasing peptide as spinal neurotransmitters of histaminergic and nonhistaminergic itch

Tasuku Akiyama, Mitsutoshi Tominaga, Kenji Takamori, Mirela Iodi Carstens, E. Carstens

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

We investigated roles for substance P (SP), gastrin-releasing peptide (GRP), and glutamate in the spinal neurotransmission of histamine-dependent and -independent itch. In anesthetized mice, responses of single superficial dorsal horn neurons to intradermal (i.d.) injection of chloroquine were partially reduced by spinal application of the α-amino-3-hydroxy-5-methyl-4- isoxazole proprionate acid (AMPA)/kainate antagonist 6-cyano-7-nitroquinoxaline- 2,3-dione (CNQX). Co-application of CNQX plus a neurokinin-1 (NK-1) antagonist produced stronger inhibition, while co-application of CNQX, NK-1, and GRP receptor (GRPR) antagonists completely inhibited firing. Nociceptive-specific and wide dynamic range-type neurons exhibited differential suppression by CNQX plus either the GRPR or NK-1 antagonist, respectively. Neuronal responses elicited by i.d. histamine were abolished by CNQX alone. In behavioral studies, individual intrathecal administration of a GRPR, NK-1, or AMPA antagonist each significantly attenuated chloroquine-evoked scratching behavior. Co-administration of the NK-1 and AMPA antagonists was more effective, and administration of all 3 antagonists abolished scratching. Intrathecal CNQX alone prevented histamine-evoked scratching behavior. We additionally employed a double-label strategy to investigate molecular markers of pruritogen-sensitive dorsal root ganglion (DRG) cells. DRG cells responsive to histamine and/or chloroquine, identified by calcium imaging, were then processed for co-expression of SP, GRP, or vesicular glutamate transporter type 2 (VGLUT2) immunofluorescence. Subpopulations of chloroquine- and/or histamine-sensitive DRG cells were immunopositive for SP and/or GRP, with >80% immunopositive for VGLUT2. These results indicate that SP, GRP, and glutamate each partially contribute to histamine-independent itch. Histamine-evoked itch is mediated primarily by glutamate, with GRP playing a lesser role. Co-application of NK-1, GRP, and AMPA receptor antagonists may prove beneficial in treating chronic itch.

Original languageEnglish (US)
Pages (from-to)80-92
Number of pages13
JournalPain
Volume155
Issue number1
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Gastrin-Releasing Peptide
Substance P
Histamine
Neurotransmitter Agents
Glutamic Acid
Chloroquine
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Vesicular Glutamate Transport Protein 2
Spinal Ganglia
Bombesin Receptors
Neurokinin-1 Receptor Antagonists
6-Cyano-7-nitroquinoxaline-2,3-dione
Isoxazoles
Posterior Horn Cells
Neurokinin-1 Receptors
Intradermal Injections
AMPA Receptors
Kainic Acid
Synaptic Transmission
Fluorescent Antibody Technique

Keywords

  • Gastrin-releasing peptide
  • Glutamate
  • Histamine
  • Itch
  • Scratching
  • Substance P

ASJC Scopus subject areas

  • Pharmacology
  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

Cite this

Roles of glutamate, substance P, and gastrin-releasing peptide as spinal neurotransmitters of histaminergic and nonhistaminergic itch. / Akiyama, Tasuku; Tominaga, Mitsutoshi; Takamori, Kenji; Carstens, Mirela Iodi; Carstens, E.

In: Pain, Vol. 155, No. 1, 01.01.2014, p. 80-92.

Research output: Contribution to journalArticle

Akiyama, Tasuku ; Tominaga, Mitsutoshi ; Takamori, Kenji ; Carstens, Mirela Iodi ; Carstens, E. / Roles of glutamate, substance P, and gastrin-releasing peptide as spinal neurotransmitters of histaminergic and nonhistaminergic itch. In: Pain. 2014 ; Vol. 155, No. 1. pp. 80-92.
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