Journal article
Pharmacological Inhibition of the Voltage-Gated Sodium Channel NaV1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome
ACS Pharmacology & Translational Science, Vol.4(4), pp.1362-1378
2021
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.
Details
- Title
- Pharmacological Inhibition of the Voltage-Gated Sodium Channel NaV1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome
- Authors
- Yan Jiang (Author) - University of QueenslandJoel Castro (Author) - Flinders UniversityLinda V Blomster (Author) - University of QueenslandAkello J Agwa (Author) - University of QueenslandJessica Maddern (Author) - Flinders UniversityGudrun Schober (Author) - Flinders UniversityVolker Herzig (Author) - University of QueenslandChun Yuen Chow (Author) - University of QueenslandFernanda C Cardoso (Author) - University of QueenslandPaula Demétrio De Souza França (Author) - Federal University of Sao PauloJunior Gonzales (Author) - Memorial Sloan Kettering Cancer CenterChristina I Schroeder (Author) - University of QueenslandSteffen Esche (Author) - Independent Consultant, Weissenfels 06667, GermanyThomas Reiner (Author) - Memorial Sloan Kettering Cancer CenterStuart M Brierley (Author) - Flinders UniversityGlenn F King (Author) - University of Queensland
- Publication details
- ACS Pharmacology & Translational Science, Vol.4(4), pp.1362-1378
- Publisher
- American Chemical Society
- DOI
- 10.1021/acsptsci.1c00072
- ISSN
- 2575-9108
- Organisation Unit
- School of Science, Technology and Engineering; Centre for Bioinnovation; University of the Sunshine Coast, Queensland
- Language
- English
- Record Identifier
- 99544108902621
- Output Type
- Journal article
Metrics
10 Record Views
InCites Highlights
These are selected metrics from InCites Benchmarking & Analytics tool, related to this output
- Collaboration types
- Domestic collaboration
- International collaboration
- Web Of Science research areas
- Chemistry, Medicinal
- Pharmacology & Pharmacy
UN Sustainable Development Goals (SDGs)
This output has contributed to the advancement of the following goals:
Source: InCites