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.