Pharmacological Inhibition of the Voltage-Gated Sodium Channel Nav1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome

The human nociceptor-specific voltage-gated sodium channel 1.7 (hNa(v)1.7) is critical for sensing various types of somatic pain, but it appears not to play a primary role in acute visceral pain. However, its role in chronic visceral pain remains to be determined. We used assay-guided fractionation to isolate a novel hNa(v)1.7 inhibitor, Tsp1a, from tarantula venom. Tsp1a is 28-residue peptide that potently inhibits hNa(v)1.7 (IC50 = 10 nM), with greater than 100-fold selectivity over hNa(v)1.3-hNa v 1.6, 45-fold selectivity over hNa(v)1.1, and 24-fold selectivity over hNa(v)1.2. Tsp1a is a gating modifier that inhibits Na(v)1.7 by inducing a hyperpolarizing shift in the voltage-dependence of channel inactivation and slowing recovery from fast inactivation. NMR studies revealed that Tsp1a adopts a classical knottin fold, and like many knottin peptides, it is exceptionally stable in human serum. Remarkably, intracolonic administration of Tsp1a completely reversed chronic visceral hypersensitivity in a mouse model of irritable bowel syndrome. The ability of Tsp1a to reduce visceral hypersensitivity in a model of irritable bowel syndrome suggests that pharmacological inhibition of hNa(v)1.7 at peripheral sensory nerve endings might be a viable approach for eliciting analgesia in patients suffering from chronic visceral pain.

Automated summary

Tsp1a, a novel inhibitor of hNa(v)1.7 isolated from tarantula venom, potently inhibits the channel's activity and completely reverses chronic visceral hypersensitivity in a mouse model of irritable bowel syndrome, suggesting that pharmacological inhibition of hNa(v)1.7 at peripheral sensory nerve endings could be a viable approach for alleviating pain in patients suffering from chronic visceral pain.