Role of presynaptic nicotinic acetylcholine receptors in the regulation of gastrointestinal motility

Presynaptic nicotinic acetylcholine receptors (nAChRs) located on cholinergic terminals facilitate the release of acetylcholine (ACh), thereby constituting a fail-safe mechanism at strategic locations, such as the neuromuscular junction, where reliable transmission is vital. Accumulating data indicate that myenteric neurons in the enteric nervous system possess not only somatodendritic nAChRs, which mediate cholinergic transmission between neurons, but also presynaptic nAChRs. Functional evidence shows that these receptors mediate a positive feedback with respect to ACh release from myenteric motoneurons, and might therefore play an important role in the regulation of gastrointestinal motility. These presynaptic nAChRs were found to be more sensitive to nicotinic ligands than somatodendritic nAChRs and could therefore be primary targets of exogenous compounds, such as nicotine. This interaction might provide a neurochemical basis for the effect of smoking on gastrointestinal motility. Another important human pharmacological implication is based on our recent observation that monoamine uptake inhibitor-type antidepressant drugs are able to inhibit presynaptic nAChRs in the enteric nervous system. The disruption of the nAChR-mediated positive feedback modulation by antidepressants might explain the frequent occurrence of constipation, a common side effect, attributed to these drugs. Clarification of the role of presynaptic nAChRs in feedback mechanisms in the enteric nervous system might be instrumental in the development of new drugs affecting gastrointestinal motility.