Ion Channels Involved in Substance P-Mediated Nociception and Antinociception

Abstract

Substance P (SP), an 11-amino-acid neuropeptide, has long been considered an effector of pain. However, accumulating studies have proposed a paradoxical role of SP in anti-nociception. Here, we review studies of SP-mediated nociception and anti-nociception in terms of peptide features, SP-modulated ion channels, and differential effector systems underlying neurokinin 1 receptors (NK1Rs) in differential cell types to elucidate the effect of SP and further our understanding of SP in anti-nociception. Most importantly, understanding the anti-nociceptive SP-NK1R pathway would provide new insights for analgesic drug development.

Keywords: NK1R; anti-nociception; nociception; pain; substance P.

Figure 1

Schematic diagram of substance P-mediated signaling and ion channels in the peripheral sensory neurons. Release of substance P (SP) in the nerve terminal acts on neurokinin 1 receptor (NK1R) via two different effector systems modulating M-type K⁺ and T-type Ca²⁺ channels. First, activated NK1R coupled to tyrosine kinase augments the M-type potassium channels, resulting in neuronal hyperpolarization. Second, activated NK1R coupled to G_i/o triggers reactive oxygen species (ROS) release from mitochondria simultaneously to augment M-type potassium channels and inhibit T-type calcium channels, which inhibits neural firing in peripheral sensory neurons.