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      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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          Author and article information

          Journal
          Neuron
          Neuron
          Elsevier BV
          08966273
          November 2014
          November 2014
          : 84
          : 4
          : 821-834
          Article
          10.1016/j.neuron.2014.10.003
          4254557
          25453842
          © 2014

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