Feed-forward inhibition: a novel cellular mechanism for the analgesic effect of substance P

Long-Jun Wu, Hui Xu, Shanelle W Ko, Megumu Yoshimura, Min Zhuo, Long-Jun Wu, Hui Xu, Shanelle W Ko, Megumu Yoshimura, Min Zhuo

Abstract

Substance P (SP) is a neuropeptide well known for its contribution to pain transmission in the spinal cord, however, less is known about the possible modulatory effects of SP. A new study by Gu and colleagues, published in Molecular Pain (2005, 1:20), describes its potential role in feed-forward inhibition in lamina V of the dorsal horn of the spinal cord. This inhibition seems to function through a direct excitation of GABAergic interneurons by substance P released from primary afferent fibers and has a distinct temporal phase of action from the well-described glutamate-dependent feed-forward inhibition. It is believed that through this inhibition, substance P can balance nociceptive output from the spinal cord.

Figures

Figure 1
Figure 1
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.

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