**10. T-type Calcium Channels**

T-type calcium channels (Cav3) are low-voltage activated calcium channels opened with small membrane depolarization and can generate Ca2+-dependent burst firing, pacemaker activity, and low-amplitude neuronal oscillation [103]. In contrast to high-threshold L-type calcium channels (long-lasting calcium channels), T-type calcium channels only mediate a "transient" calcium influx, with the voltage threshold about −60 with slower activation. T channels also form a window current in the resting membrane potential controlling the sub-threshold neuronal excitability.

The α1 subunit consists of the major channel pore of T-type calcium channels, allowing for calcium influx through it. The channel pore-forming α subunits include Cav3.1, Cav3.2, and Cav3.3 encoded by calcium voltage-gated channel subunit alpha1 G (CACNA1G), H, and I, respectively. T-type calcium channels were first found in small sensory neurons by Carbone and Lux in 1984 [104]. Subsequently, functional expression of T-type channels was confirmed in nociceptive DRG neurons, with Cav3.2 as the predominant isoform. Nelson et al. further characterized the expression profile of T channels and indicated that a subtype of DRG neurons highly expressed T channels, named T-rich cells, which were also highly sensitive to capsaicin and ATP stimuli [105]. Those T-rich cells are mainly small-diameter neurons with narrower APs and after depolarizing potentials during the action potential falling phase. Altering gating parameters or directly increasing the amplitude of the T current can result in burst firing and neuronal excitability [105]. Inhibiting the T-type channels can effectively reduce the neuropathic and inflammatory pain [106–108].

Recently, Huang et al. demonstrated that T channels were modulated by SP [77]. The authors found that SP release in damaging tissue would act on NK1R via Gi/o to release mitochondria reactive oxygen species, which further inhibited the T channels. This study revealed SP-mediated anti-nociception in a subtype of small-diameter sensory neurons. Further studies are required to determine whether mediumto large-diameter sensory neurons also show the same modulation of SP in T-type calcium channels.

### **11. Conclusions**

Accumulating evidence has shown SP-mediated anti-nociception in both the CNS and PNS. However, SP has a mixed effect of pro-nociception and anti-nociception in the nervous system. Especially, blocking NK1R signaling in the CNS can result in adverse outcomes. In contrast, the anti-nociceptive effect of SP in the PNS has been well characterized, especially in muscle. Applying SP to muscle-afferent DRG neurons enhances the M-channel outward current, which further hyperpolarizes the neurons. Accordingly, locally targeting the SP-NK1R pathway on muscle afferent neurons could be a promising analgesic strategy.

**Author Contributions:** C.-C.C. composed the idea and wrote the manuscript. C.-T.C. drafted the manuscript and figure. B.-Y.J. prepared the information of table.

**Funding:** This work was supported by a grant from the Institute of Biomedical Sciences, Academia Sinica (IBMS-CRC107-P01), and grants from the Ministry of Science and Technology, Taiwan (MOST105-2320-B-001-018-MY3, MOST107-2319-B-001-002, and MOST108-2321-B-001-005).

**Acknowledgments:** We thank the staff of the Medical Art Room at Institute of Biomedical Sciences, Academia Sinica, for the scientific illustration in Figure 1.

**Conflicts of Interest:** The authors declare no conflict of interest.
