title: Phosphorylation of NMDA receptor GluN2B subunit at Tyr1472 is important for trigeminal processing of itch.
abstract: Itch and pain are intimately related and may share similar peripheral and central mechanisms and pathways. However, it has been believed that synaptic glutamate release from a group of peripheral nociceptors is required to sense pain and suppress itch. Although we previously demonstrated that phosphorylation of GluN2B subunits of the NMDA receptor at Tyr1472 is important for central sensitization in a neuropathic pain model of mice with a knock-in mutation of the Tyr1472 site to phenylalanine of GluN2B (Y1472F-KI), the role of NMDA receptors in itch transmission remains unknown. Here, we demonstrated that the scratching behaviors elicited by various pruritogens applied to the cheek and c-fos expression in the region innervated by the trigeminal nerve were markedly attenuated in the Y1472F-KI mice. The c-fos immunoreactivity was co-localized with the receptor of gastrin-releasing peptide (GRP). Scratching behaviors evoked by chloroquine were inhibited by the NMDA receptor antagonists D-AP5 and CP101,606 and by the Src kinase inhibitor PP2. Direct activation of the trigeminal region by intracisternal administration of NMDA and GRP induced robust scratching behaviors, both of which were reduced by the GRP receptor antagonist RC-3095. Taken together, the data obtained in this present study are the first to demonstrate that phosphorylation of GluN2B subunit at Tyr1472 is important for trigeminal transmission of itch and suggest that the NMDA receptor activation occurs upstream of the GRP-GRP receptor pathway.
authors.affiliation: Department of Medical Chemistry, Kansai Medical University, Hirakata, 573-1010, Japan.
authors.forename: Akitoshi
authors.identifier: 0000-0002-5432-4137
authors.initials: A
authors.lastname: Inoue
authors.affiliation: Department of Medical Chemistry, Kansai Medical University, Hirakata, 573-1010, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Uchida
authors.affiliation: Drug Innovation Center, Graduate School of Pharmaceutical Science, Osaka University, Suita, Japan.
authors.forename: Takanobu
authors.initials: T
authors.lastname: Nakazawa
authors.affiliation: Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Medical Chemistry, Kansai Medical University, Hirakata, 573-1010, Japan. ito@hirakata.kmu.ac.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Ito
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D019886:Gastrin-Releasing Peptide / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D051379:Mice; D009437:Neuralgia / Q000378:metabolism; D010766:Phosphorylation; D011537:Pruritus / Q000235:genetics / Q000503:physiopathology*; D018004:Receptors, Bombesin / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects
chemical_list: C121001:NR2B NMDA receptor; D018004:Receptors, Bombesin; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D019886:Gastrin-Releasing Peptide
keywords: Y1472F-KI mice; c-fos; gastrin-releasing peptide; glutamate; pruritus