Stimuli that elicit itch are detected by sensory neurons that innervate the skin. This information is processed by the spinal cord; however, the way in which this occurs is still poorly understood. Here we investigated the neuronal pathways for itch neurotransmission, in particular the contribution of the neuropeptide somatostatin. We find that in the periphery, somatostatin is exclusively expressed in Nppb neurons, and we demonstrate that Nppb/somatostatin-cells function as pruriceptors. Employing chemogenetics, pharmacology and cell-specific ablation methods, we demonstrate that somatostatin potentiates itch by inhibiting inhibitory dynorphin neurons, which results in disinhibition of GRPR neurons. Furthermore, elimination of somatostatin from primary afferents and/or from spinal interneurons demonstrates differential involvement of the peptide released from these sources in itch and pain. Our results define the neural circuit underlying somatostatin-induced itch, and characterize a contrasting anti-nociceptive role for the peptide.

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Highlights d Chemogenetic activation of mast cells induces itch responses d Receptors for mast cell mediators are specifically expressed by Nppb neurons d Serotonin, leukotriene, and sphingosine-1-phosphate stimulate Nppb neurons d Mast cell activation via GRP spinal cord signaling elicits itch behavior

Highlights d NGN2-BRN3A expression in human stem cells induces homogeneous sensory neurons (iSNs) d Three kinds of iSNs can be produced, including subtypes coexpressing TRPM8 and PIEZO2 d TRPM8 and PIEZO2 unexpectedly mark a subset of sensory neurons in humans, but not mice d iSNs from PIEZO2-deficient patients are insensitive to mechanical stimuli