Localisation and function of melatonin in the murine colon

Abstract

Melatonin is an indoleamine hormone that also serves as a neurotransmitter. It is naturally synthesised from tryptophan (Wurtman et al., 1964). Melatonin is well known to play a key role in the regulation of sleep patterns. However, little is known about its role in the colon. Studies in the 1970s showed that melatonin was present in the intestinal mucosa of rats and humans (Bubenik et al., 1977; Raikhlin et al., 1975), but provided no specific location of the mucosal source of melatonin. In 2008, using electrochemical methods, it was shown that melatonin is present and released from the ileum mucosa (Patel et al., 2008). There have also been limited studies on the functional role of melatonin in the intestinal tract. While some studies indicated that melatonin directs contraction, others indicate that it influences relaxation; and others suggest melatonin acts as an antagonist of 1 mucosal serotonin (Bubenik et al., 1989). The aim of this study is to understand the localisation of colonic melatonin and its role in governing colonic motility in the mouse. For the first time in mice, the synthesis enzymes, AANAT and HIOMT, are identified in the colon; and in the vicinity of EC cells in the mucosal layer via immunohistochemistry. This suggests that melatonin is synthesised within the EC cells. The locations of EC cells and melatonin expression were in close proximity to one another. Melatonin was discovered to accumulate in higher levels in the murine proximal colon as compared to the distal colon, and this is related to the number of EC cells. Functional studies presented here involve a novel in-depth look into the mechanisms governing melatonin effects on various colonic motility patterns. Melatonin shows a net positive effect on contractile activity triggered by both serotonin and EFS. This is building on top of past observational knowledge about the dual effects of melatonin. Previous studies have not made a deeper investigation into the mechanisms of melatonin activity in the presence of melatonin and external stimuli (EFS). In these induced motility tones, the effects appear to be mainly mediated through the upregulation of the contractile response. These effects are mediated by neuronal signalling pathways and not by the underlying musculature. Melatonin was discovered to have the opposite effect on the propagation of spontaneous CMMCs. It decreases the magnitude of spontaneous CMMC responses in the proximal colon, decreasing the velocity of propagation of CMMC waves down the length of the colon. However, in fecal pellet distention induced propulsion, melatonin has been shown to boost colonic transit times, promoting motility. Melatonin receptors are shown to be involved in both processes. Our current results indicate that there is a significant role for melatonin in the colon in terms of motility regulation, and that it has the potential to be an important therapeutic target within the bowel.

Date of Award	2016
Original language	English
Awarding Institution	University of Brighton
Supervisor	Bhavik Patel (Supervisor) & Mark Yeoman (Supervisor)