title: Roles of glutamate, substance P, and gastrin-releasing peptide as spinal neurotransmitters of histaminergic and nonhistaminergic itch.
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.
authors.affiliation: Department of Neurobiology, Physiology & Behavior, University of California, Davis, CA, USA Institute for Environmental and Gender Specific Medicine, Juntendo University Graduate School of Medicine, Urayasu, Chiba 279-0021, Japan.
authors.forename: Tasuku
authors.initials: T
authors.lastname: Akiyama
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Tominaga
authors.forename: Kenji
authors.initials: K
authors.lastname: Takamori
authors.forename: Mirela Iodi
authors.initials: MI
authors.lastname: Carstens
authors.forename: E
authors.initials: E
authors.lastname: Carstens
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D001839:Bombesin / Q000031:analogs & derivatives / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000473:pathology*; D019886:Gastrin-Releasing Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011537:Pruritus / Q000378:metabolism* / Q000473:pathology*; D013373:Substance P / Q000378:metabolism*; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism
chemical_list: D018501:Antirheumatic Agents; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D010880:Piperidines; D050599:Vesicular Glutamate Transport Protein 2; C071363:bombesin (6-14), Tpi(6)-Leu(13)-psi(CH2NH)-Leu(14)-; C103788:3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidine; D013373:Substance P; D018698:Glutamic Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D019886:Gastrin-Releasing Peptide; D002738:Chloroquine; D001839:Bombesin
keywords: Gastrin-releasing peptide; Glutamate; Histamine; Itch; Scratching; Substance P
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