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

Zhong Qiu Zhao, Xian Yu Liu, Joseph Jeffry, W. K.Ajith Karunarathne, Jin Lian Li, Admire Munanairi, Xuan Yi Zhou, Hui Li, Yan Gang Sun, Li Wan, Zhen Yu Wu, Seungil Kim, Fu Quan Huo, Ping Mo, Devin M. Barry, Chun Kui Zhang, Ji Young Kim, N. Gautam, Kenneth J. Renner, Yun Qing LiZhou Feng Chen

Research output: Contribution to journalArticle

52 Scopus citations

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 Ca2+ 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.

Original languageEnglish
Pages (from-to)821-834
Number of pages14
JournalNeuron
Volume84
Issue number4
DOIs
StatePublished - Nov 19 2014

Fingerprint Dive into the research topics of 'Descending control of itch transmission by the serotonergic system via 5-HT1A-facilitated GRP-GRPR signaling'. Together they form a unique fingerprint.

  • Cite this

    Zhao, Z. Q., Liu, X. Y., Jeffry, J., Karunarathne, W. K. A., Li, J. L., Munanairi, A., Zhou, X. Y., Li, H., Sun, Y. G., Wan, L., Wu, Z. Y., Kim, S., Huo, F. Q., Mo, P., Barry, D. M., Zhang, C. K., Kim, J. Y., Gautam, N., Renner, K. J., ... Chen, Z. F. (2014). Descending control of itch transmission by the serotonergic system via 5-HT1A-facilitated GRP-GRPR signaling. Neuron, 84(4), 821-834. https://doi.org/10.1016/j.neuron.2014.10.003