title: Descending control of itch transmission by the serotonergic system via 5-HT1A-facilitated GRP-GRPR signaling.
abstract: Central serotonin (5-hydroxytryptophan, 5-HT) modulates somatosensory transduction, but how it achieves sensory modality-specific modulation remains unclear. Here we report that enhancing serotonergic tone via administration of 5-HT potentiates itch sensation, whereas mice lacking 5-HT or serotonergic neurons in the brainstem exhibit markedly reduced scratching behavior. Through pharmacological and behavioral screening, we identified 5-HT1A as a key receptor in facilitating gastrin-releasing peptide (GRP)-dependent scratching behavior. Coactivation of 5-HT1A and GRP receptors (GRPR) greatly potentiates subthreshold, GRP-induced Ca(2+) transients, and action potential firing of GRPR(+) neurons. Immunostaining, biochemical, and biophysical studies suggest that 5-HT1A and GRPR may function as receptor heteromeric complexes. Furthermore, 5-HT1A blockade significantly attenuates, whereas its activation contributes to, long-lasting itch transmission. Thus, our studies demonstrate that the descending 5-HT system facilitates GRP-GRPR signaling via 5-HT1A to augment itch-specific outputs, and a disruption of crosstalk between 5-HT1A and GRPR may be a useful antipruritic strategy.
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Zhong-Qiu
authors.initials: ZQ
authors.lastname: Zhao
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Xian-Yu
authors.initials: XY
authors.lastname: Liu
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Jeffry
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: W K Ajith
authors.initials: WK
authors.lastname: Karunarathne
authors.affiliation: Department of Anatomy, Histology and Embryology, K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jin-Lian
authors.initials: JL
authors.lastname: Li
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Admire
authors.initials: A
authors.lastname: Munanairi
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Xuan-Yi
authors.initials: XY
authors.lastname: Zhou
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anatomy, Histology and Embryology, K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Yan-Gang
authors.initials: YG
authors.lastname: Sun
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wan
authors.affiliation: Department of Anatomy, Histology and Embryology, K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Seungil
authors.initials: S
authors.lastname: Kim
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Fu-Quan
authors.initials: FQ
authors.lastname: Huo
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, the Affiliated Nanhai Hospital of Southern Medical University, Foshan 528000, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Mo
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Devin M
authors.initials: DM
authors.lastname: Barry
authors.affiliation: Department of Anatomy, Histology and Embryology, K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Chun-Kui
authors.initials: CK
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: N
authors.initials: N
authors.lastname: Gautam
authors.affiliation: Department of Biology, University of South Dakota, Vermillion, SD 57069, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Renner
authors.affiliation: Department of Anatomy, Histology and Embryology, K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yun-Qing
authors.initials: YQ
authors.lastname: Li
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: chenz@wustl.edu.
authors.forename: Zhou-Feng
authors.initials: ZF
authors.lastname: Chen
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D019886:Gastrin-Releasing Peptide / Q000378:metabolism*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011537:Pruritus / Q000378:metabolism* / Q000503:physiopathology; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D018004:Receptors, Bombesin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: D018004:Receptors, Bombesin; D044282:Receptor, Serotonin, 5-HT1A; D019886:Gastrin-Releasing Peptide