SCN10A: A pivotal therapeutic target for analgesic drug development

• Gene Information: The sodium voltage-gated channel alpha subunit 10 (SCN10A) gene encodes the Nav1.8 sodium channel protein, which is crucial for pain signal transmission in peripheral sensory neurons.
• Protein Expression: The NaV1.8 sodium channels are predominantly expressed in dorsal root ganglion (DRG) and trigeminal ganglion neurons, which are primarily nociceptive. The NaV1.8 channels display stringent tissue specificity, with barely detectable expression in the central nervous system, cardiac and skeletal muscle.
• Signaling Pathway: Under physiological conditions, Nav1.8 maintains moderate activity to support physiological nociceptive defense. During tissue injury and inflammation, Nav1.8 is upregulated with a decreased activation threshold and enhanced aberrant firing, which directly induces pain hypersensitivity and spontaneous pain.
• Therapeutic Inhibition: Suzetrigine produces analgesia through highly selective Nav1.8 blockade, interrupting peripheral nociceptive signaling to mitigate pain before signals are relayed to the brain. As a peripherally acting agent, its mechanism differs from opioids, which trigger central euphoria and stimulatory effects.

SCN10A

• The bacterial artificial chromosome (BAC) clone CH17-178G5 containing the whole human SCN10A genome sequence was randomly inserted into rat genome in B-Tg(hSCN10A),Scn10a KO rats.
• The exons 2-28 of rat Scn10a that encode the full-length protein were knocked out in B-Tg(hSCN10A),Scn10a KO rats.

• Human SCN10A mRNA is exclusively detectable in dorsal root ganglia (DRG)  of B-Tg(hSCN10A),Scn10a KO rats, but not in wild-type SD rats.

Species specific analysis of SCN10A gene expression in wild-type SD rats and B-Tg(hSCN10A),Scn10a KO rats by RT-qPCR. Dorsal root ganglions (DRG) were collected from wild-type SD rats (+/+) and B-Tg(hSCN10A),Scn10a KO rats(Tg; -/-) (male, 10-12-week-old, n=6). The mRNA expression of rat Scn10a was detectable only in SD rats, but not in B-Tg(hSCN10A),Scn10a KO rats. The mRNA expression of human SCN10A was detectable only in B-Tg(hSCN10A),Scn10a KO rats, but not in SD rats. Values are expressed as mean ± SEM.

Experimental schedule for the induction of postoperative pain model and in vivo efficacy of Suzetrigine analog in SD rats and B-Tg(hSCN10A),Scn10a KO rats. The rats underwent a 3-day acclimation period in test cages. Surgery was conducted on rat hind paws on Day 0 to generate a postoperative pain model. Pain thresholds were measured with the Von Frey test 2 h before compound administration. Suzetrigine analog was orally administered, and follow-up Von Frey threshold measurements were performed at 1 h and 2 h after dosing.

Postoperative pain modeling and analgesic effects of Suzetrigine analog in wild-type SD rats and B-Tg(hSCN10A),Scn10a KO rats. In wild-type SD rats and B-Tg(hSCN10A),Scn10a KO rats, plantar incision markedly reduced mechanical pain thresholds. In wild-type SD rats, Suzetrigine analog at 60 mpk significantly alleviated postoperative pain with an analgesic effect lasting up to 2 h, whereas 10 mpk showed no effect. In B-Tg(hSCN10A),Scn10a KO rats, Suzetrigine analog at 10 mpk significantly alleviated postoperative pain with an analgesic effect lasting up to 2 h. B-Tg(hSCN10A),Scn10a KO rats provide a powerful preclinical model for in vivo evaluation of the efficacy of targeted human SCN10A analgesic drugs. *P < 0.05, **P < 0.01, ***P < 0.001.