Impact of cannabinoid type 1 receptor (CB1R) signalling on intestinal inflammation and motility

Background: This thesis investigated the role of CB1R signalling in suppressing intestinal inflammation and restoring normal motility in the context of postoperative ileus (POI) and inflammatory bowel disease (IBD). POI characterised by halted gut movement following surgery, primarily due to surgical manipulation and neurogenic factors suppressing enteric neuronal impulses. While IBD resulted from a multifactorial interplay of genetic predisposition, immune-mediated inflammation, and environmental factors, leading to dysregulated intestinal motility. Methodology: To understand the impact of pharmacological CB1R regulation on gut function, we examined the regulation of leucocyte trafficking molecules including cell adhesion molecules (CAMs) on HEK293T cells and their cognate integrin ligands on Jurkat T cells. This was expanded to assess functional changes using cell adhesion assays in vitro model. Based on CB1R-mediated changes in CAMs expression and cell adherence, we next examined potential underlying mechanisms via NF?B activation by dual luciferase reporter assay. To examine potential changes in motility within the inflamed gut associated with CB1R activation, we initially established an ex vivo model using explanted human and rat colonic tissue to study the effect of CB1R on intestinal smooth muscle contractions. Finally, we employed a zebrafish intestinal motility in vivo model to examine changes in motility associated with intestinal inflammation. Results: CB1R antagonism with AM6545 suppressed MAdCAM-1, ICAM-1, and VCAM-1, expression in TNF treated HEK293T cells in vitro model. In contrast, CB1R activation with WIN55,212-2 upregulated ICAM-1 and VCAM-1 mRNA coinciding with increased NF?B transcriptional activity. In the zebrafish in vivo model, chemically induced colitis led to intestinal shortening and decreased transit time measured following microgavage procedure. Conclusion: This investigation shed light on the therapeutic potential of CB1R blockade in attenuating intestinal inflammation and restoring motility.