QX-314 inhibits acid-induced activation of esophageal nociceptive C fiber neurons

Youtian Hu, Xiaoyun Yu, Shaoyong Yu

Research output: Contribution to journalArticle

Abstract

Introduction: Acid reflux in the esophagus can induce painful sensations such as heartburn and non-cardiac chest pain. These nociceptive symptoms are initiated by activation of TRPV1-positive afferent C fibers in the esophagus. The present study aimed to explore a novel C fiber inhibition approach. We hypothesized that activation of TRPV1 by acid enabled QX-314, a membrane impermeable sodium channel blocker, to inhibit acid-induced activation of esophageal nociceptive C fiber neurons. Method: We determined the inhibitory effect of QX-314 in the presence of acid in guinea pig esophageal nociceptive vagal jugular C fiber neurons by both patch clamp recording in neuron soma and by extra-cellular recording at nerve terminals. Key Results: Our data demonstrated QX-314 alone did not inhibit sodium currents. However, when applied along with capsaicin to activate TRPV1, QX-314 was able to block sodium currents in esophageal-specific jugular C fiber neurons. We then showed that in the presence of acid, QX-314 significantly blocked acid-evoked activation of jugular C fiber neurons. This effect was attenuated by TRPV1 antagonist AMG9810, suggesting acid-mediated inhibitory effect of QX-314 was TRPV1-dependent. Finally, we provided evidence at nerve endings that acid-evoked action potential discharges in esophageal jugular C fibers were inhibited by QX-314 when applied in the presence of acid. Conclusion and Inferences: Our data demonstrated that activation of TRPV1 by acid enabled membrane impermeable sodium channel blocker QX-314 to inhibit acid-induced activation in esophageal nociceptive C fibers. This supports a localized application of QX-314 in the esophagus to block esophageal nociception in acid reflux disorders.

Original languageEnglish (US)
Article numbere13543
JournalNeurogastroenterology and Motility
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Unmyelinated Nerve Fibers
Neurons
Acids
Neck
Sodium Channel Blockers
Esophagus
QX-314
Sodium
Heartburn
Nociception
Membranes
Nerve Endings
Capsaicin
Carisoprodol
Chest Pain
Evoked Potentials
Action Potentials
Guinea Pigs

Keywords

  • acid
  • esophagus
  • nociceptor
  • QX-314
  • TRPV1

ASJC Scopus subject areas

  • Physiology
  • Endocrine and Autonomic Systems
  • Gastroenterology

Cite this

QX-314 inhibits acid-induced activation of esophageal nociceptive C fiber neurons. / Hu, Youtian; Yu, Xiaoyun; Yu, Shaoyong.

In: Neurogastroenterology and Motility, 01.01.2019.

Research output: Contribution to journalArticle

@article{d9406174f9fc46edaa23c26d79877eec,
title = "QX-314 inhibits acid-induced activation of esophageal nociceptive C fiber neurons",
abstract = "Introduction: Acid reflux in the esophagus can induce painful sensations such as heartburn and non-cardiac chest pain. These nociceptive symptoms are initiated by activation of TRPV1-positive afferent C fibers in the esophagus. The present study aimed to explore a novel C fiber inhibition approach. We hypothesized that activation of TRPV1 by acid enabled QX-314, a membrane impermeable sodium channel blocker, to inhibit acid-induced activation of esophageal nociceptive C fiber neurons. Method: We determined the inhibitory effect of QX-314 in the presence of acid in guinea pig esophageal nociceptive vagal jugular C fiber neurons by both patch clamp recording in neuron soma and by extra-cellular recording at nerve terminals. Key Results: Our data demonstrated QX-314 alone did not inhibit sodium currents. However, when applied along with capsaicin to activate TRPV1, QX-314 was able to block sodium currents in esophageal-specific jugular C fiber neurons. We then showed that in the presence of acid, QX-314 significantly blocked acid-evoked activation of jugular C fiber neurons. This effect was attenuated by TRPV1 antagonist AMG9810, suggesting acid-mediated inhibitory effect of QX-314 was TRPV1-dependent. Finally, we provided evidence at nerve endings that acid-evoked action potential discharges in esophageal jugular C fibers were inhibited by QX-314 when applied in the presence of acid. Conclusion and Inferences: Our data demonstrated that activation of TRPV1 by acid enabled membrane impermeable sodium channel blocker QX-314 to inhibit acid-induced activation in esophageal nociceptive C fibers. This supports a localized application of QX-314 in the esophagus to block esophageal nociception in acid reflux disorders.",
keywords = "acid, esophagus, nociceptor, QX-314, TRPV1",
author = "Youtian Hu and Xiaoyun Yu and Shaoyong Yu",
year = "2019",
month = "1",
day = "1",
doi = "10.1111/nmo.13543",
language = "English (US)",
journal = "Neurogastroenterology and Motility",
issn = "1350-1925",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - QX-314 inhibits acid-induced activation of esophageal nociceptive C fiber neurons

AU - Hu, Youtian

AU - Yu, Xiaoyun

AU - Yu, Shaoyong

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Introduction: Acid reflux in the esophagus can induce painful sensations such as heartburn and non-cardiac chest pain. These nociceptive symptoms are initiated by activation of TRPV1-positive afferent C fibers in the esophagus. The present study aimed to explore a novel C fiber inhibition approach. We hypothesized that activation of TRPV1 by acid enabled QX-314, a membrane impermeable sodium channel blocker, to inhibit acid-induced activation of esophageal nociceptive C fiber neurons. Method: We determined the inhibitory effect of QX-314 in the presence of acid in guinea pig esophageal nociceptive vagal jugular C fiber neurons by both patch clamp recording in neuron soma and by extra-cellular recording at nerve terminals. Key Results: Our data demonstrated QX-314 alone did not inhibit sodium currents. However, when applied along with capsaicin to activate TRPV1, QX-314 was able to block sodium currents in esophageal-specific jugular C fiber neurons. We then showed that in the presence of acid, QX-314 significantly blocked acid-evoked activation of jugular C fiber neurons. This effect was attenuated by TRPV1 antagonist AMG9810, suggesting acid-mediated inhibitory effect of QX-314 was TRPV1-dependent. Finally, we provided evidence at nerve endings that acid-evoked action potential discharges in esophageal jugular C fibers were inhibited by QX-314 when applied in the presence of acid. Conclusion and Inferences: Our data demonstrated that activation of TRPV1 by acid enabled membrane impermeable sodium channel blocker QX-314 to inhibit acid-induced activation in esophageal nociceptive C fibers. This supports a localized application of QX-314 in the esophagus to block esophageal nociception in acid reflux disorders.

AB - Introduction: Acid reflux in the esophagus can induce painful sensations such as heartburn and non-cardiac chest pain. These nociceptive symptoms are initiated by activation of TRPV1-positive afferent C fibers in the esophagus. The present study aimed to explore a novel C fiber inhibition approach. We hypothesized that activation of TRPV1 by acid enabled QX-314, a membrane impermeable sodium channel blocker, to inhibit acid-induced activation of esophageal nociceptive C fiber neurons. Method: We determined the inhibitory effect of QX-314 in the presence of acid in guinea pig esophageal nociceptive vagal jugular C fiber neurons by both patch clamp recording in neuron soma and by extra-cellular recording at nerve terminals. Key Results: Our data demonstrated QX-314 alone did not inhibit sodium currents. However, when applied along with capsaicin to activate TRPV1, QX-314 was able to block sodium currents in esophageal-specific jugular C fiber neurons. We then showed that in the presence of acid, QX-314 significantly blocked acid-evoked activation of jugular C fiber neurons. This effect was attenuated by TRPV1 antagonist AMG9810, suggesting acid-mediated inhibitory effect of QX-314 was TRPV1-dependent. Finally, we provided evidence at nerve endings that acid-evoked action potential discharges in esophageal jugular C fibers were inhibited by QX-314 when applied in the presence of acid. Conclusion and Inferences: Our data demonstrated that activation of TRPV1 by acid enabled membrane impermeable sodium channel blocker QX-314 to inhibit acid-induced activation in esophageal nociceptive C fibers. This supports a localized application of QX-314 in the esophagus to block esophageal nociception in acid reflux disorders.

KW - acid

KW - esophagus

KW - nociceptor

KW - QX-314

KW - TRPV1

UR - http://www.scopus.com/inward/record.url?scp=85060354897&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060354897&partnerID=8YFLogxK

U2 - 10.1111/nmo.13543

DO - 10.1111/nmo.13543

M3 - Article

C2 - 30663188

AN - SCOPUS:85060354897

JO - Neurogastroenterology and Motility

JF - Neurogastroenterology and Motility

SN - 1350-1925

M1 - e13543

ER -