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Title: The role of adenosine 5'-triphosphate in mechanosensory transduction in the rat colorectum
Author: Wynn, Gregory Robert
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2005
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Adenosine 5'-triphoshate (ATP), along with other mediators, plays a role in peripheral sensory mechanisms and has been implicated in mechanosensory transduction in the urinary system. P2X2 and P2X3 receptors are expressed on small diameter sensory neurons in the dorsal root ganglia (DRG) and these are known to supply the rat colorectum. ATP appears to be particularly important during inflammation. This work aimed to investigate whether purinergic signalling contributes to mechanosensory transduction in the rat colorectum and whether these mechanisms play a more important role during colitis. The degree of interaction between ATP and other mediators that activate visceral afferents was also studied. Novel in-vitro rat colorectal preparations (either normal or colitic) were used to investigate whether ATP is released from the mucosa in response to distension and whether this contributes to sensory nerve discharge. Pelvic nerve recordings were made during application of ATP and other mediators to the preparations and computer analysis allowed calculation of single unit activity. Results indicated that P2X3 receptors present on DRG neurons were up-regulated during colitis. Distension of the colorectum led to pressure-dependent increases in ATP which were substantially higher in the colitis preparations. Distension-evoked pelvic nerve excitation was mimicked by application of ATP and these discharges were potentiated by purinergic agonists and by ATPase inhibition and attenuated by various P2X antagonists. These effects were exaggerated in the inflammatory setting. Single fibre analysis showed that high threshold fibres were particularly affected by methylene ATP, suggesting correlation between purinergic activation and nociceptive stimuli. 5-hydroxytryptamine, capsaicin and protons when coapplied with ATP may act synergistically. It is concluded that ATP contributes to mechanosensory transduction in the rat colorectum, particularly during inflammation and this is probably associated with pain. The underlying mechanisms appear to involve distension- evoked release of ATP as well as an increase in the number of DRG neurons expressing P2X3 receptors during colitis, especially those containing calcitonon gene-related peptide (CGRP). The pattern of neuronal activation to a variety of agents suggests that visceral afferents are polymodal but the receptor expression on their terminals can vary markedly.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available