Acid sensitivity of the spinal dorsal root ganglia C‐fiber nociceptors innervating the guinea pig esophagus

• Published in: Neurogastroenterology and motility 2015-06, Vol.27 (6), p.865-874
• Main Authors: Ru, F., Banovcin, P., Kollarik, M.
• Format: Article
• Language: English
• Subjects: acid sensing; Acid Sensing Ion Channels - drug effects; Acid Sensing Ion Channels - genetics; Acid Sensing Ion Channels - metabolism; Animals; esophagus; Esophagus - drug effects; Esophagus - innervation; Ganglia, Spinal - drug effects; Ganglia, Spinal - metabolism; Guinea Pigs; Hydrochloric Acid - pharmacology; Hydrogen-Ion Concentration; Mucous Membrane; Nerve Fibers, Unmyelinated - drug effects; Nerve Fibers, Unmyelinated - metabolism; Nerve Tissue Proteins - drug effects; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons - drug effects; Neurons - metabolism; nociceptor; Nociceptors - drug effects; Nociceptors - metabolism; pain; Potassium Channels, Tandem Pore Domain - drug effects; Potassium Channels, Tandem Pore Domain - genetics; Potassium Channels, Tandem Pore Domain - metabolism; Receptors, G-Protein-Coupled - drug effects; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; RNA, Messenger - drug effects; RNA, Messenger - metabolism; Solutions - pharmacology; TRPV Cation Channels - antagonists & inhibitors
• ISSN: 1350-1925; 1365-2982
• DOI: 10.1111/nmo.12561

Background Gastroesophageal reflux can cause high acidity in the esophagus and trigger heartburn and pain. However, because of the esophageal mucosal barrier, the acidity at the nerve terminals of pain‐mediating C‐fibers in esophageal mucosa is predicted to be substantially lower. We hypothesized that the esophageal dorsal root ganglia (DRG) C‐fibers are activated by mild acid (compared to acidic reflux), and express receptors and ion channels highly sensitive to acid. Methods Extracellular single unit recordings of activity originating in esophageal DRG C‐fiber nerve terminals were performed in the innervated esophagus preparation ex vivo. Acid was delivered in a manner that bypassed the esophageal mucosal barrier. The expression of mRNA for selected receptors in esophagus‐specific DRG neurons was evaluated using single cell RT‐PCR. Key Results Mild acid (pH = 6.5–5.5) activated esophageal DRG C‐fibers in a pH‐dependent manner. The response to mild acid at pH = 6 was not affected by the TRPV1 selective antagonist iodo‐resiniferatoxin. The majority (70–95%) of esophageal DRG C‐fiber neurons (TRPV1‐positive) expressed mRNA for acid sensing ion channels (ASIC1a, ASIC1b, ASIC2b, and/or ASIC3), two‐pore‐domain (K2P) potassium channel TASK1, and the proton‐sensing G‐protein coupled receptor OGR1. Other evaluated targets (PKD2L1, TRPV4, TASK3, TALK1, G2A, GPR4, and TDAG8) were expressed rarely. Conclusions & Inferences Guinea pig esophageal DRG C‐fibers are activated by mild acid via a TRPV1‐independent mechanism, and express mRNA for several receptors and ion channels highly sensitive to acid. The high acid sensitivity of esophageal C‐fibers may contribute to heartburn and pain in conditions of reduced mucosal barrier function. Because of the esophageal mucosal barrier, the acidity at the nerve terminals of esophageal pain‐mediating C‐fibers is predicted to be relatively mild compared to acidic gastroesophageal reflux. We evaluated the response to mild acid (pH = 6.5–5.5) by single fiber recordings and the expression of mRNA for acid‐sensitive receptors and ion channels by single cell RT‐PCR in the guinea pig esophageal DRG C‐fibers. Guinea pig esophageal DRG C‐fibers are activated by mild acid via a TRPV1‐independent mechanism, and express mRNA for several receptors and ion channels highly sensitive to acid (ASICs, TASK1 and OGR1).