Underlying mechanism of the cyclic migrating motor complex inSuncus murinus: a change in gastrointestinal pH is the key regulator

Abstract

In the fasted gastrointestinal (GI) tract, a characteristic cyclical rhythmic migrating motor complex (MMC) occurs in an ultradian rhythm, at 90–120 min time intervals, in many species. However, the underlying mechanism directing this ultradian rhythmic MMC pattern is yet to be completely elucidated. Therefore, this study aimed to identify the possible causes or factors that involve in the occurrence of the fasting gastric contractions by using Suncus murinus a small model animal featuring almost the same rhythmic MMC as that found in humans and dogs. We observed that either intraduodenal infusion of saline at pH 8 evoked the strong gastric contraction or continuously lowering duodenal pH to 3‐evoked gastric phase II‐like and phase III‐like contractions, and both strong contractions were essentially abolished by the intravenous administration of MA 2029 (motilin receptor antagonist) and D‐Lys3‐GHRP6 (ghrelin receptor antagonist) in a vagus‐independent manner. Moreover, we observed that the prostaglandin E2‐alpha (PGE2‐ α) and serotonin type 4 (5HT4) receptors play important roles as intermediate molecules in changes in GI pH and motilin release. These results suggest a clear insight mechanism that change in the duodenal pH to alkaline condition is an essential factor for stimulating the endogenous release of motilin and governs the fasting MMC in a vagus‐independent manner. Finally, we believe that the changes in duodenal pH triggered by flowing gastric acid and the release of duodenal bicarbonate through the involvement of PGE2‐ α and 5HT4 receptor are the key events in the occurrence of the MMC.

Advances in the physiology of gastric emptying

“…Motilin acts on multiple sites including the myenteric neurons and smooth muscles in a species‐dependent fashion . Its action on myenteric plexus neurons initiates phase III of the gastric MMC that promotes gastric emptying of indigestible food residues.…”

“…114 Motilin release is due to duodenal alkalization that oc- Motilin acts on multiple sites including the myenteric neurons and smooth muscles in a species-dependent fashion. 116 Its action on myenteric plexus neurons initiates phase III of the gastric MMC that promotes gastric emptying of indigestible food residues. Phase III of the MMC is strongly inhibited by the gastric inhibitory vagovagal reflex that is activated upon ingestion of food.…”

Motilin Comparative Study: Structure, Distribution, Receptors, and Gastrointestinal Motility

“…Mondal et al. ( 99 ) examined the association of duodenal pH and gastric phase III contractions by motilin and reported the mechanisms for motilin release by a change in duodenal luminal pH as follows: acidification of the duodenal lumen by gastric acid stimulates the synthesis of PGE 2, which decreases the release of gastric acid and simultaneously increases 5-HT release from enteric 5-HT neurons and mucosal enterochromaffin cells; 5-HT activates the release of bicarbonate from mucosal cells by activation of the 5-HT 4 receptor and the released bicarbonate increases the luminal pH; finally, alkalinization of the lumen stimulates the release of motilin to cause the gastric contraction, although the mechanisms of motilin release by luminal alkalinization have not been clarified. The interval of appearance of gastric phase III of the MMC is a required time that duodenal acidification finally causes alkalinization in the duodenum through the pathway including PGE 2 , 5-HT/5-HT 4 receptor and bicarbonate.…”

“…The interval of appearance of gastric phase III of the MMC is a required time that duodenal acidification finally causes alkalinization in the duodenum through the pathway including PGE 2 , 5-HT/5-HT 4 receptor and bicarbonate. The increase in the 5-HT concentration in the duodenal lumen by PGE 2 is also thought to contribute to the initiation of duodenal MMC ( 99 ).…”

“…In in vitro experiments, on the other hand, the local actions of motilin on smooth muscle cells and enteric neurons can be examined. Based on the results of functional studies mainly used dogs, rabbits and Suncus , the mechanisms of GI motility-stimulating actions by motilin are divided into three pathways ( 6 , 7 , 71 , 99 , 116 , 117 ) ( Figure 3 ): (i) the action on MLN-Rs located on smooth muscle cells; (ii) the action on MLN-Rs located on enteric neurons although detailed neural networks have not been proven, as a result, ACh released from cholinergic neurons causes contraction through the muscarinic receptor; and (iii) the activation of the vago-vagal reflex pathways followed by stimulating vagal efferent neurons connecting to the enteric neurons. The presence of 5-HT 3 receptors has been demonstrated in the terminals of vagus afferent neurons ( 115 ), and motilin-induced contraction in the vagus-intact stomach, but not in the vagotomized stomach, was decreased by a 5-HT 3 receptor antagonist ( 94 ).…”