Schematic diagram of SP-driven feed-forward inhibition in lamina V of the spinal cord dorsal horn. Sensory information starts from dorsal root ganglion (DRG) neurons, is relayed by spinal cord dorsal horn neurons and then is projecting to the brain. The intense painful stimulation of primary afferent, mostly Aδ- and C- fibers, induced the release of SP in lamina I and V. On the one hand, SP directly excites projection neurons in laminar I, thereby inducing pronociceptive response. On the other hand, SP in laminar V excites inhibitory interneurons in lamina V, through NK1 receptor (NK1R) and the following signaling pathway involved pertussis toxin-sensitive Gi/Go protein and possible downstream targets Ca2+ or K+ channels. The firing of these interneurons releases GABA and/or glycine, activate GABAA receptor (GABAAR) and/or glycine receptor (GlyR), and initiates feed-forward inhibition in the projection neurons ascending to the brain. The inhibitory interneuron is in green and the projection neuron is in red.