Pharmacological inhibition of the voltage-gated sodium channel Na(v)1.7 alleviates chronic visceral pain in a rodent model of irritable bowel syndrome Journal Article
| Authors: | Jiang, Y.; Castro, J.; Blomster, L. V.; Agwa, A. J.; Maddern, J.; Schober, G.; Herzig, V.; Chow, C. Y.; Cardoso, F. C.; Demétrio De Souza França, P. D.; Gonzales, J.; Schroeder, C. I.; Esche, S.; Reiner, T.; Brierley, S. M.; King, G. F. |
| Article Title: | Pharmacological inhibition of the voltage-gated sodium channel Na(v)1.7 alleviates chronic visceral pain in a rodent model of irritable bowel syndrome |
| Abstract: | The human nociceptor-specific voltage-gated sodium channel 1.7 (hNaV1.7) 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 hNaV1.7 inhibitor, Tsp1a, from tarantula venom. Tsp1a is 28-residue peptide that potently inhibits hNaV1.7 (IC50 = 10 nM), with greater than 100-fold selectivity over hNaV1.3-hNaV1.6, 45-fold selectivity over hNaV1.1, and 24-fold selectivity over hNaV1.2. Tsp1a is a gating modifier that inhibits NaV1.7 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 hNaV1.7 at peripheral sensory nerve endings might be a viable approach for eliciting analgesia in patients suffering from chronic visceral pain. © 2021 American Chemical Society. |
| Keywords: | analgesic; irritable bowel syndrome; chronic visceral pain; voltage-gated sodium channel 1.7; venom peptide; gating modifier |
| Journal Title: | ACS Pharmacology & Translational Science |
| Volume: | 4 |
| Issue: | 4 |
| ISSN: | 2575-9108 |
| Publisher: | American Chemical Society |
| Date Published: | 2021-08-13 |
| Start Page: | 1362 |
| End Page: | 1378 |
| Language: | English |
| DOI: | 10.1021/acsptsci.1c00072 |
| PROVIDER: | scopus |
| PMCID: | PMC8369682 |
| PUBMED: | 34423271 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 October 2021 -- Source: Scopus |
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