TY - JOUR
T1 - Pharmacological Inhibition of the Voltage-Gated Sodium Channel NaV1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome
AU - Jiang, Yan
AU - Castro, Joel
AU - Blomster, Linda V.
AU - Agwa, Akello J.
AU - Maddern, Jessica
AU - Schober, Gudrun
AU - Herzig, Volker
AU - Chow, Chun Yuen
AU - Cardoso, Fernanda C.
AU - Demétrio De Souza França, Paula
AU - Gonzales, Junior
AU - Schroeder, Christina I.
AU - Esche, Steffen
AU - Reiner, Thomas
AU - Brierley, Stuart M.
AU - King, Glenn F.
N1 - Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/8/13
Y1 - 2021/8/13
N2 - 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.
AB - 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.
KW - analgesic
KW - chronic visceral pain
KW - gating modifier
KW - irritable bowel syndrome
KW - venom peptide
KW - voltage-gated sodium channel 1.7
UR - http://www.scopus.com/inward/record.url?scp=85108541259&partnerID=8YFLogxK
U2 - 10.1021/acsptsci.1c00072
DO - 10.1021/acsptsci.1c00072
M3 - Article
AN - SCOPUS:85108541259
SN - 2575-9108
VL - 4
SP - 1362
EP - 1378
JO - ACS Pharmacology and Translational Science
JF - ACS Pharmacology and Translational Science
IS - 4
ER -