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

Abstract

Human mGluR5, GABA(A,B), and CB(1,2) receptors are abundantly expressed along the vago-vagal neural pathway and involved in the triggering of TLESRs. These findings are not only in line with the central side effects observed during treatment with reflux inhibitors such as GABA(B) receptor agonists and mGluR5 antagonists, but also suggest that peripherally acting compounds may be effective.

Localization and role of metabotropic glutamate receptors subtype 5 in the gastrointestinal tract

“…The use of the mGluR5 antagonist, MPEP, has highlighted a decrease in reflux events through inhibition of transient lower sphincter relaxation (TLESR)[17,20]. Immunohistochemical localization of mGluR5 along the vago-vagal neural pathway has been found in human tissues indicating a potential peripheral effect of mGluR5 modulators[21]. In a trial involving a small group of patients with gastroesophageal reflux disease (GERD), use of ADX10059 a mGluR5 negative allosteric modulator, was associated with an improvement in clinical symptoms characterized by reduced acid reflux[22].…”

Pharmacological Options Beyond Proton Pump Inhibitors in Children with Gastroesophageal Reflux Disease

“…This reflex can be blocked by an interaction with 5 metabotropic Glutamate receptors (mGluR5), A and B alfa-aminobutyric acid receptors (GABA (A, B)) and cannabinoid ones (CB 1,2). The above receptors recently proved to be widely expressed (except GABA(A) receptors) in the neurons of LES myenteric plexus, of cellular bodies and of nerve fibers of the nodose ganglion (except GABA(A) ones), in the dorsal motor and in the solitary tract nuclei [18]. Pharmacological molecules which interact with these receptors may thus determine a reduction of GER through a peripheral action but may, concurrently, also cause central side effects.…”

Novel Upcoming Therapies

“…A wide range of receptors is involved in triggering TLESR including gamma-aminobutiric acid B (GABA B ), metabotropic glutamate receptor 5 (mGlucR5), cannabinoid (CB), cholecystokinin (CCK), 5-hydroxytryptamine-4, muscarinic, and opioid [54].…”