Metoclopramide is a dopamine receptor antagonist and has been approved by the FDA to treat nausea and vomiting in patients with gastroesophageal reflux disease or diabetic gastroparesis by increasing gastric motility.. Metoclopramide works by antagonizing central and peripheral dopamine-two receptors (D2) in the medullary chemoreceptor trigger zone in the area postrema, usually stimulated by levodopa or apomorphine. It achieves this by decreasing the sensitivity of visceral afferent nerves that transmit from the gastrointestinal system to the vomiting center in the area postrema in the chemoreceptor trigger zone. In addition to antagonizing dopamine receptors, metoclopramide is an antagonist at 5HT3 (type 3 serotonin receptors) and an agonist at 5HT4 receptors. Metoclopramide's agonism of 5-HT4 receptors in the gastrointestinal tract can stimulate gastrointestinal motility, including enhancing gastric emptying and promoting peristalsis. This effect can be beneficial in conditions associated with delayed gastric emptying, such as gastroparesis, and it may help relieve symptoms like nausea and vomiting. Activation of 5-HT4 receptors can also lead to the release of acetylcholine, which further enhances smooth muscle contraction in the gut. In the gastrointestinal tract, when serotonin (5-HT) binds to 5-HT4 receptors in the GI tract, it initiates intracellular signaling through a G-protein-coupled mechanism. 5-HT4 receptors are typically coupled to Gs proteins. Activation of Gs proteins stimulates adenylate cyclase (AC), leading to increased production of cyclic AMP (cAMP) from ATP. The increase in cAMP levels activates protein kinase A (PKA) through the cAMP-PKA pathway. PKA activation can lead to smooth muscle contraction in the GI tract. This increased contractility promotes peristalsis and enhances gastric emptying by propelling food and digestive contents through the GI tract.

Metoclopramide Serotonin Neuronal Pathway References