title: Cross-inhibition of NMBR and GRPR signaling maintains normal histaminergic itch transmission.
abstract: We previously showed that gastrin-releasing peptide receptor (GRPR) in the spinal cord is important for mediating nonhistaminergic itch. Neuromedin B receptor (NMBR), the second member of the mammalian bombesin receptor family, is expressed in a largely nonoverlapping pattern with GRPR in the superficial spinal cord, and its role in itch transmission remains unclear. Here, we report that Nmbr knock-out (KO) mice exhibited normal scratching behavior in response to intradermal injection of pruritogens. However, mice lacking both Nmbr and Grpr (DKO mice) showed significant deficits in histaminergic itch. In contrast, the chloroquine (CQ)-evoked scratching behavior of DKO mice is not further reduced compared with Grpr KO mice. These results suggest that NMBR and GRPR could compensate for the loss of each other to maintain normal histamine-evoked itch, whereas GRPR is exclusively required for CQ-evoked scratching behavior. Interestingly, GRPR activity is enhanced in Nmbr KO mice despite the lack of upregulation of Grpr expression; so is NMBR in Grpr KO mice. We found that NMB acts exclusively through NMBR for itch transmission, whereas GRP can signal through both receptors, albeit to NMBR to a much lesser extent. Although NMBR and NMBR(+) neurons are dispensable for histaminergic itch, GRPR(+) neurons are likely to act downstream of NMBR(+) neurons to integrate NMB-NMBR-encoded histaminergic itch information in normal physiological conditions. Together, we define the respective function of NMBR and GRPR in itch transmission, and reveal an unexpected relationship not only between the two receptors but also between the two populations of interneurons in itch signaling.
authors.affiliation: Center for the Study of Itch, and Departments of Anesthesiology.
authors.forename: Zhong-Qiu
authors.initials: ZQ
authors.lastname: Zhao
authors.affiliation: Center for the Study of Itch, and Departments of Anesthesiology, Department of Anesthesiology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, People's Republic of China, and.
authors.forename: Li
authors.initials: L
authors.lastname: Wan
authors.affiliation: Center for the Study of Itch, and Departments of Anesthesiology.
authors.forename: Xian-Yu
authors.initials: XY
authors.lastname: Liu
authors.affiliation: Center for the Study of Itch, and Departments of Anesthesiology.
authors.forename: Fu-Quan
authors.initials: FQ
authors.lastname: Huo
authors.affiliation: Center for the Study of Itch, and Departments of Anesthesiology, Department of Anatomy, Histology and Embryology, and K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China.
authors.forename: Hui
authors.identifier: http://orcid.org/0000-0001-9083-7776
authors.initials: H
authors.lastname: Li
authors.affiliation: Center for the Study of Itch, and Departments of Anesthesiology.
authors.forename: Devin M
authors.identifier: http://orcid.org/0000-0002-3140-6121
authors.initials: DM
authors.lastname: Barry
authors.affiliation: Radiation Oncology, and.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Krieger
authors.affiliation: Center for the Study of Itch, and Departments of Anesthesiology.
authors.forename: Seungil
authors.initials: S
authors.lastname: Kim
authors.affiliation: Center for the Study of Itch, and Departments of Anesthesiology.
authors.forename: Zhong-Chun
authors.initials: ZC
authors.lastname: Liu
authors.affiliation: Radiology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Jinbin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Radiation Oncology, and.
authors.forename: Buck E
authors.initials: BE
authors.lastname: Rogers
authors.affiliation: Department of Anatomy, Histology and Embryology, and K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China.
authors.forename: Yun-Qing
authors.initials: YQ
authors.lastname: Li
authors.affiliation: Center for the Study of Itch, and Departments of Anesthesiology, Psychiatry, Developmental Biology, chenz@wustl.edu.
authors.forename: Zhou-Feng
authors.initials: ZF
authors.lastname: Chen
mesh_terms: D000818:Animals; D019886:Gastrin-Releasing Peptide / Q000235:genetics / Q000378:metabolism*; D006632:Histamine; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition; D059225:Nociception / Q000502:physiology*; D020671:Posterior Horn Cells / Q000502:physiology*; D011537:Pruritus / Q000139:chemically induced / Q000503:physiopathology*; D018004:Receptors, Bombesin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018004:Receptors, Bombesin; D019886:Gastrin-Releasing Peptide; D006632:Histamine
keywords: GRP; GRPR; NMB; NMBR; cross-inhibition; itch