**8. Ion Channels Involved in SP-Mediated Anti-Nociception**

The role of SP in anti-nociception has been confirmed in both the CNS and the PNS. In the CNS, the analgesic effect of SP is mainly associated with opioid-dependent pathways, although other studies also demonstrated the involvement of GABAAR and glycine receptors in the lamina V of the spinal cord [90,97].

**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 Gi/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.

In the PNS, SP can act on NK1R via either tyrosine kinase or Gi/o effector system to potentiate the inhibitory M-type potassium channels and inhibit excitatory T-type calcium channels in a specific subset of sensory neurons [76,77]. In muscle afferent DRG neurons, the SP-NK1R signaling is coupled with tyrosine kinase to enhance M-type potassium channel activity [57]. Enhancing the M-type potassium current and inhibiting the T-type calcium current results in dampening neuronal excitability, in turn further leading to an anti-nociceptive effect (Figure 1).
