**7. Ion Channels Involved in SP-Mediated Nociception**

SP has a well-known role in the transmission of nociceptive information in the spinal cord. In the supraspinal level, microinjection of SP in the rostral ventromedial medulla (RVM) has also been found to induce hyperalgesia via descending facilitation mechanisms in a glutamate- and GABAA-dependent manner [92,93]. Furthermore, SP release is increased in the spinal dorsal horn after peripheral nociceptive stimulation [94]. Overall, the amount of nociceptive neurotransmitter released by primary afferent nerve terminals determines the level of pain. The release of SP in the spinal dorsal horn would interact with glutamate to enhance peripheral inputs. Previously, SP and glutamate were found to co-exist in small-diameter DRG neurons and their nerve terminals in the

spinal dorsal horn [95]. Glutamate acts as the molecule transmitting the fast excitatory signal, whereas SP modulates relatively slow excitatory synapse responses [96]. Besides, SP signaling can enhance the *N*-methyl-*D*-aspartate (NMDA) channel function leading to greater pain sensitivity [78–81]. Thus, the two transmitters, glutamate and SP, are considered to interact and convey the nociceptive information in the spinal cord.

In the peripheral system, SP is an important element in neurogenic inflammation causing extravasation and sensory neuron sensitization. During inflammatory processes, inflammatory cells and peripheral nerve terminals release SP, which, in turn, modulates a variety of ion channels rendering sensitization of sensory neurons in an autocrine or paracrine manner. In the PNS, SP mainly exists in the small sensory nociceptors. Release of SP can act on NK1R via differential intracellular mechanisms to potentiate the channel activities of TRPV1 [84–86], Nav1.8 [83], and L- and N-type calcium channels [87] in a subset of small-diameter DRG neurons, thereby resulting in hyperalgesia. SP could also decease the activity of low-threshold potassium channel (kv4) in capsaicin-sensitive DRG neurons and thus sensitize the nociceptors [88]. In the orofacial region, SP can potentiate the P2X3 receptor in TG neurons, leading to elevated pain sensitivity [89]. In summary, SP predominantly acts on peripheral sensory small neurons (presumably nociceptors) to excite the neurons, thereby increasing nociceptive responses.
