Descending control of itch transmission by the serotonergic system via 5-HT1A-facilitated GRP-GRPR signaling.

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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.

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Journal

Journal ID (iso-abbrev): Neuron

Title: Neuron

Publisher: Elsevier BV

ISSN (Electronic): 1097-4199

ISSN (Print): 0896-6273

Publication date (Electronic): Nov 19 2014

Volume: 84

Issue: 4

Affiliations

[1 ] 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.

[2 ] Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.

[3 ] Department of Anatomy, Histology and Embryology, K. K. Leung Brain Research Centre, The Fourth Military Medical University, Xi'an 710032, China.

[4 ] Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA.

[5 ] 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.

[6 ] 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.

[7 ] 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.

[8 ] Department of Biology, University of South Dakota, Vermillion, SD 57069, USA.

[9 ] 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.

Article

Publisher Item ID: S0896-6273(14)00901-5 Mid ID: NIHMS634080

DOI: 10.1016/j.neuron.2014.10.003

PMC ID: 4254557

PubMed ID: 25453842

SO-VID: 3fee1730-bf50-4793-b970-e8c3e0276592

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