The role of GABA_A receptors in the control of transient lower oesophageal sphincter relaxations in the dog

Abstract

Background and purpose: Transient lower oesophageal sphincter relaxations (TLESRs) are triggered by activation of mechanosensitive gastric vagal afferents and are the major cause of gastroesophageal reflux and therefore an important target for therapeutic intervention in gastroesophageal reflux disease (GERD). Activation of the metabotropic GABA B receptor has shown to inhibit TLESRs. The aim of the present study was to assess the role of the ionotropic GABA A receptor in the regulation of TLESRs. Experimental approach: TLESRs were quantified using Dentsleeve manometry in dogs, and GABA A agonists were given i.v. prior to gastric distension. Immunohistochemistry and RT-PCR were used to localize GABA A receptors in the dog nodose ganglion, the source of vagal afferents which initiate TLESRs. Key results: The prototypical GABA A agonist muscimol produced a dose-dependent inhibition of TLESRs ranging from 19 to 56%. The two other GABA A agonists evaluated, isoguvacine and 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP), as well as the GABA A positive allosteric modulator diazepam, had no major effects on TLESRs. Evaluation of higher doses was limited by emesis (THIP and isoguvacine) or restlessness/sedation (diazepam). Of the predominant GABA A receptor subunits (a, b and g components), a and b but not g were detected in the dog nodose ganglion by RT-PCR, while immunohistochemistry in addition demonstrated nerve fibres expressing the g subunit. Conclusions and implications:The present observations demonstrate that GABA A receptors exert an inhibitory control of TLESRs. These results warrant further studies using GABA A isoform-selective agonists to define the identity of receptors involved.

The Influence of Esomeprazole and Cisapride on Gastroesophageal Reflux During Anesthesia in Dogs

“…24,25 Transient LES relaxations are part of a vago-vagal reflex, triggered by distension of the stomach, and are found to be the main mechanism of both acid and nonacidic RE both in healthy volunteers and patients. 24,25 Acidic and nonacidic RE occurred in 18/61 dogs (29.5%). These findings parallel those previously reported in the veterinary literature.…”

Localization of mGluR5, GABAB, GABAA, and cannabinoid receptors on the vago‐vagal reflex pathway responsible for transient lower esophageal sphincter relaxation in humans: an immunohistochemical study

“…GABA A induces fast synaptic ionotropic inhibition upon activation, and the receptor consists of various subunits 13,26 . In contrast to GABA B receptors, no GABA A α 1 was present in the myenteric plexus and nodose ganglion, which is comparable to the absence of these receptors in the periphery in dogs 13 . The lack of effect of peripherally acting GABA A antagonists on TLESR rates in dogs substantiates the absence of peripheral GABA A receptors on the vago‐vagal reflex arch 13 …”

“…GABA A induces fast synaptic ionotropic inhibition upon activation, and the receptor consists of various subunits 13,26 . In contrast to GABA B receptors, no GABA A α 1 was present in the myenteric plexus and nodose ganglion, which is comparable to the absence of these receptors in the periphery in dogs 13 .…”

“…More importantly, recent clinical studies have clearly demonstrated that GABA B ‐receptor agonists baclofen and lesogaberan and mGluR5 antagonists inhibit TLESRs thereby reducing the number of reflux episodes and symptoms in healthy patients and GERD patients 8–12 . Activation of GABA A receptors, known to mediate fast postsynpatic inhibition, also leads to an inhibition of TLESRs in dogs, but the effect of GABA A agonists on the inhibition of TLESRs has not been studied in humans 13 . Lastly, Δ 9 ‐tetrahydrocannabinol, a receptor agonist of cannabinoid 1 and 2 receptor (CB1, CB2), reduced the number of TLESRs in humans and dogs 14 …”

4-Aminobutyrate Aminotransferase (ABAT): Genetic and Pharmacological Evidence for an Involvement in Gastro Esophageal Reflux Disease

“…The neurotransmitter GABA is involved in the control of the LES [51]. Signaling through both GABA A [52] and especially GABA B receptors reduces TLESRs, as shown with GABA B receptor agonists [53]. TLESRs are the major motility factor underlying GERD [54] and these relaxations result in an increased frequency of reflux episodes [55] thereby causing esophageal mucosal damage.…”