GABAB receptors - peripheral and central targets for controlling gastroesophageal reflux

Abstract

Inhibition of acid secretion has been the major treatment for gastroesophageal reflux disease (GERD) for many years since the discovery of drugs acting on the gastric parietal cell. However, reflux occurs during transient lower esophageal sphincter (LES) relaxations. These are episodic events triggered by meal ingestion that are unassociated with swallowing. Only in the past ten years has attention been focused on inhibition of reflux through inhibition of transient LES relaxations as an alternative to inhibition of acid secretion for treatment of GERD. This slow evolution of approach may be attributable to the lack of complete understanding of the neural mechanisms underlying transient LES relaxations. It is evident that transient LES relaxations are vagally mediated and are triggered episodically by a central pattern generator, which receives input from gastric mechanoreceptors. A number of pharmacological treatments has been shown to reduce their occurrence, including CCK1 and muscarinic receptor antagonists, NO synthase (NOS) inhibitors, and morphine. Unfortunately a specific site of action cannot yet be ascribed to these treatments, and they are of limited potential clinical benefit owing to side effects. We have recently shown that GABA(B) receptor agonists potently reduce triggering of transient LES relaxations with minimal side effects in three species. We have further shown that they have specific actions at different points centrally and peripherally on the vagal afferent and efferent pathway involved in transient LES relaxations. A particularly promising point of intervention is on the peripheral endings of gastric mechanoreceptors, where GABA(B) receptors have a direct inhibitory action on the mechanotransduction mechanism implicated in trigering of transient LES relaxations. Thus triggering of reflux could potentially be reduced at the source of the stimulus without intervention in the CNS. As new subtypes and variants of the GABA(B) receptor become apparent from molecular studies, the potential for achieving this becomes more feasible. Functional studies also provide indications that GABA(B) receptor subtypes exist which may be exploited for clinical benefit.