Open AccessPharmacological Inhibition of the Voltage-Gated Sodium Channel NaV1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome
Author(s) -
Yan Jiang,
Joel Castro,
Linda V. Blomster,
Akello J. Agwa,
Jessica Maddern,
Gudrun Schober,
Volker Herzig,
Chun Yuen Chow,
Fernanda C. Cardoso,
Paula Demétrio De Souza França,
Junior Gonzales,
Christina I. Schroeder,
Steffen Esche,
Thomas Reiner,
Stuart M. Brierley,
Glenn F. King
Publication year - 2021
Publication title -
acs pharmacology and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.271
H-Index - 10
ISSN - 2575-9108
DOI - 10.1021/acsptsci.1c00072
Subject(s) - irritable bowel syndrome , sodium channel , visceral pain , rodent model , medicine , chronic pain , pharmacology , sodium , chemistry , physical therapy , nociception , receptor , organic chemistry
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 (IC 50 = 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.