Investigating novel therapeutic targets for treatment of visceral pain.

Abdominal pain is a common symptom of gastrointestinal disorders such as Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS). However, despite the many treatments for inflammation in IBD and disordered motility in IBS patients, few therapies target abdominal pain directly, and many commonly used analgesics are contraindicated due to gut related side effects. Consequently, the management of pain in IBD and IBS patients remains a significant clinical challenge. The aim of this thesis is to evaluate novel therapeutic approaches to the treatment of visceral pain in gastrointestinal diseases by: • Studying the effect of calcium activated potassium (KCa) channel openers on the activation of colonic afferents by prototypic algogenic stimuli. • Examining the effect of inflammatory mediators (angiotensin II and matrix metalloproteinase 1) upregulated during colitis on colonic afferent activity. Pre-treatment with NS 1619, an opener of BKCa (subtype of KCa channels) had no effect on the colonic afferent response to ATP. Similarly, the combined IKCa/SKCa opener SKA 31 had no effect on the response to ATP and bradykinin and colonic ramp distension. In contrast subsequent pre-treatment with the KCNQ channel opener retigabine inhibited the colonic afferent response to ATP, bradykinin and ramp distension. Furthermore, in a separate set of experiments application of NS 1619 and SKA 31 abolished ongoing peristaltic activity demonstrating the drugs were pharmacologically active at the concentration and routes of administration in our studies. Findings from this work indicate that KCNQ but not KCa channel openers may have therapeutic potential for the treatment of abdominal pain in gastrointestinal disease by inhibiting the activation of colonic nociceptors. Next, we studied the pro-nociceptive potential of angiotensin II (Ang II) and matrix metalloproteinase-1 (MMP1) by examining their effect on colonic afferent activity and mobilisation of intracellular Ca2+ in sensory neurons isolated from dorsal root ganglia (DRGs). Ang II elicited a robust increase in colonic afferent activity including fibres subsequently characterized as nociceptors by their co-sensitivity to noxious distension and the algogenic mediator capsaicin. This effect was inhibited by angiotensin AT1 but not AT2 receptor antagonists indicating that Ang II may contribute to the production of abdominal pain in IBD through the activation of AT1 receptors. MMP1 caused a marked increase in intracellular Ca2+ in DRG neurons classified as nociceptors by their co-sensitivity to capsaicin. This effect was blocked by pre-treatment with the protease activated receptor-1 (PAR1) receptor antagonist SCH 79797. However, neither the application of MMP1 or the PAR1 agonist, TRAP-6 produced a direct activation of colonic afferent activity despite expression of PAR1 receptors in colonic projecting sensory neurons. Further studies are therefore warranted to understand the consequences of MMP1 mediated PAR1 receptor activation on colonic sensory nerve activity and abdominal pain.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2022

Author dc:creator

• Bhebhe, Charity Ntando

Advisor dc:contributor.advisor

• Bulmer, David

• Visceral pain
• ion channels
• angiotensin II
• matrix metalloproteinases

Licence

• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.92613

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/345191