In mammals, somatosensory input activates feedback and feed-forward inhibitory circuits within the spinal cord dorsal horn to modulate sensory processing and thereby affecting sensory perception by the brain. Conventionally, feedback and feed-forward inhibitory activity evoked by somatosensory input to the dorsal horn is believed to be driven by glutamate, the principle excitatory neurotransmitter in primary afferent fibers. Substance P (SP), the prototypic neuropeptide released from primary afferent fibers to the dorsal horn, is regarded as a pain substance in the mammalian somatosensory system due to its action on nociceptive projection neurons. Here we report that endogenous SP drives a novel form of feed-forward inhibitory activity in the dorsal horn. The SP-driven feed-forward inhibitory activity is long-lasting and has a temporal phase distinct from glutamate-driven feed-forward inhibitory activity. Compromising SPdriven feed-forward inhibitory activity results in behavioral sensitization. Our findings reveal a fundamental role of SP in recruiting inhibitory activity for sensory processing, which may have important therapeutic implications in treating pathological pain conditions using SP receptors as targets.Feedback/feed-forward inhibitory modulation driven by glutamate has been well studied in the dorsal horn of the spinal cord [1][2][3]. Little is know whether feedback/feedforward inhibitory active may be driven in a glutamateindependent manner. A number of neuropeptides including substance P (SP) are also released from nociceptive primary afferent fibers [4]. SP has been regarded as a pain substance for decades [5][6][7], as supported by studies, including chemical ablation of lamina I neurons expressing the SP receptors [8], genetic disruption of the genes encoding substance P [9] and its receptors [10]. The nociceptive function of SP is mainly attributed to the activation of NK1 receptors (NK1R) that are expressed on nociceptive projection neurons located in lamina I of the
