 Abstract | The patterns of motor activity in the lower gastrointestinal tract of mammals and the mechanisms underlying their generation are incompletely understood. In this thesis, experiments were performed to provide greater insight into the role of the enteric nervous system in the generation of different propulsive motor patterns in the isolated guinea pig and human lower gastrointestinal tract. Chapter 1 focuses on a review of the current literature.
In Chapter 2, we revealed the presence of a novel form of colonic peristalsis that was surprisingly preserved despite complete blockade of major excitatory neurotransmitters (acetylcholine, tachykinins) at both enteric neuro-neuronal and neuro-muscular junctions. It was also shown that following blockade of major excitatory neuro-neuronal and neuro-muscular transmitters an intrinsic oral-aboral polarity underlying neurogenic propulsive motor patterns was always preserved.
In Chapters 3-4, the role of endogenous serotonin in the generation and propagation of colonic peristalsis was investigated. It was found that in preparations acutely depleted of all endogenous serotonin, peristalsis was still preserved with remarkably few deficits. We also demonstrated that selective antagonists of 5-HT3 and 5-HT4 receptors could still exert a temporary blockade of peristalsis despite the absence of any detectable endogenous serotonin. These raise support for the notion that 5-HT3 and 5-HT4 receptors can display constitutive activity and the antagonists can behave as inverse agonists.
Experiments in Chapters 5 were conducted on isolated segments of human bowel and the patterns of motor activity characterised in terminal ileum and colon ex vivo. Long segments of bowel were preserved ex vivo which allowed us to preserve enteric neural activity and record propulsive neurogenic motor patterns. From our small bowel studies, we report in this thesis that propagating motor patterns are only preserved in longer segments of bowel tissue, suggesting that an intact neural circuitry is vital for their generation.
Experiments on the human colon ex vivo allowed for characterisation of the motor activity in what we considered 'experimental control tissue' and compared these activities with those obtained from colonic specimens from patients with slow transit constipation (STC) (Chapter 6). We have recorded similar motor activities and contractile patterns, even in specimens from patients with STC. The presence of an underlying contractile activity that appeared similar to that seen in healthy controls raises the possibility that the aetiology underlying slow transit constipation may be induced by alterations in extrinsic neural inputs, rather than any overt dysfunction of the ENS. These experiments pave the way for an exciting future of experimentation.
A summary and discussion of the above experiments form the final chapter.
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