Abstract
Gastrointestinal motility is regulated by neural factors and humoral factors. Both motilin and ghrelin improve gastrointestinal motility, but many issues remain unclear. We prepared human motilin receptor transgenic (Tg) mice and performed experiments evaluating the effects of motilin, erythromycin (EM), and ghrelin. EM and ghrelin promoted gastric emptying (GE) when administered either peripherally or centrally to Tg mice. Atropine (a muscarinic receptor antagonist) counteracted GE induced by centrally administered EM, but not that induced by peripherally administered EM. The administration of EM in this model promoted the effect of mosapride (a selective serotonin 5-hydroxytryptamine 4 (5-HT4) receptor agonist), and improved loperamide (a μ-opioid receptor agonist)-induced gastroparesis. The level of acyl-ghrelin was significantly attenuated by EM administration. Thus, we have established an animal model appropriate for the evaluation of motilin receptor agonists. These data and the model are expected to facilitate the identification of novel compounds with clinical potential for relieving symptoms of dyspepsia and gastroparesis.
Highlights
Gastrointestinal motility is regulated by contraction and relaxation of the smooth muscle of the gastrointestinal tract and by neural and humoral factors such as peptide hormones
Takeshita et al reported that, in the human gastrointestinal tract, motilin receptors were observed in the muscle layer and myenteric plexus, and ghrelin receptors were observed in the mucosa, muscle layer, and myenteric plexus [14]
Our current experiment was performed using only EM; motilin was not employed. The basis for this distinction between the effect of EM and motilin in our model is unknown, and contrasts with a report showing that EM and motilin have similar effects on isolated stomach [19]. These results suggest that, in vitro, EM and motilin behave presumably via direct action on motilin receptor (MLNR), but that, in vivo, additional elements affect the response to these drugs
Summary
Gastrointestinal motility is regulated by contraction and relaxation of the smooth muscle of the gastrointestinal tract and by neural and humoral factors such as peptide hormones. Erythromycin (EM), one of the motilides, is commonly used as a gastrointestinal function-improving agent, many issues, including EM’s mechanism of action, remain unclear. Both motilin and ghrelin act as promoters of gastrointestinal motility, but rodents lack a motilin and motilin receptor (MLNR) [1], making it difficult to study the function (and mechanism of action) of motilides in rodent animal models or to determine a correlation between motilide and ghrelin activities. Matsuura et al have reported the molecular binding mechanism of motilin and EM to MLNR, as well as that of ghrelin to the growth hormone secretagogues receptor (GHSR) [7,8,9,10,11,12,13].
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