Synaptic control of spinal GRPR⁺ neurons by local and long-range inhibitory inputs

Spinal gastrin-releasing peptide receptor-expressing (GRPR⁺) neurons play an essential role in itch signal processing. However, the circuit mechanisms underlying the modulation of spinal GRPR⁺ neurons by direct local and long-range inhibitory inputs remain elusive. Using viral tracing and electrophysiological approaches, we dissected the neural circuits underlying the inhibitory control of spinal GRPR⁺ neurons. We found that spinal galanin⁺ GABAergic neurons form inhibitory synapses with GRPR⁺ neurons in the spinal cord and play an important role in gating the GRPR⁺ neuron-dependent itch signaling pathway. Spinal GRPR⁺ neurons also receive inhibitory inputs from local neurons expressing neuronal nitric oxide synthase (nNOS). Moreover, spinal GRPR⁺ neurons are gated by strong inhibitory inputs from the rostral ventromedial medulla. Thus, both local and long-range inhibitory inputs could play important roles in gating itch processing in the spinal cord by directly modulating the activity of spinal GRPR⁺ neurons.