Expected Therapeutic Use of GABA Agonists and Antagonists for Gut Motility Disorders

Abstract

The gut motility is controled by the autonomic nervous system, such as sympathetic and parasympathetic neurons, and the enteric nervous systems. Parasympathetic neurons are very important for regulation of gut motility. Acetylcholine (ACh) released from parasympathetic postganglionic cholinergic nerve terminals produces contractions of smooth muscles and stimulates gut motility. Most postganglionic sympathetic adrenergic nerves form a terminal network, mainly around the myenteric ganglia (1, 2). Noradrenaline (NA) released from adrenergic nerve terminals presynaptically inhibits the release of ACh from the pre- and postganglionic parasympathetic cholinergic nerve terminals, through α2-adrenoceptors (3, 4). The enteric nervous system contains a variety of intrinsic neurons, and has structural and chemical features similar to those of the central nervous system (2). Several reviews have focussed on the possible role of GABA as a neurotransmitter in the peripheral nervous systems, particularly in the enteric nervous system (5–10), and the criteria required to establish GABA as a neurotransmitter have been fulfilled. These criteria are: 1) the occurrence of GABA and its decarboxylating enzyme, glutamic acid decarboxylase (GAD) within neurons; 2) the neuronal release of GABA; 3) the neuronal and glial uptake of GABA and its inactivation by GABA transaminase (GABA-T) as mechanisms by which GABA is removed from the synaptic cleft and conserved for reuse; and 4) electrical stimulus-induced depolarization of the neuronal membrane, which is mimicked by GABA and antagonized by blockers.