Cannabinoids as potential new therapeutics of gastrointestinal motility and inflammatory disorders

Cannabinoids show potential as new treatments for inflammatory bowel disease (IBD),exerting several favourable effects in the gut, including anti-inflammatory and antimotilityeffects. The main difficulty with cannabinoids is their psychotropic side effects,but access to the brain may be prevented by conjugating the cannabinoid to a bulkygroup such as a dendrimer. The aims of this thesis were to investigate the mechanism by which cannabinoids reduce gut motility and to investigate whether cannabinoids protect the intestine from inflammatory-damage. A further aim was to determine whether cannabinoids remain pharmacologically active when conjugated to a dendrimer. All cannabinoids used (apart from arachidonoylcyclopropylamide and (-)WIN 55,212-2) caused a concentration-dependent reduction in the size of electrically-stimulated contractions in the guinea-pig ileum. The responses were not blocked by CB1, CB2, CBe(putative endothelial cannabinoid receptor) or GPR55 antagonists, suggesting that none of these receptors were involved in mediating cannabinoid responses. PSN 375963 reduced carbachol-induced contraction, suggesting that the GPR119 may be present on ileum smooth muscle. (+)WIN 55,212-2 was shown to protect the guinea-pig ileum from hydrogen peroxide-induced damage but this protection was not blocked by CB1, CB2, CBe or GPR55 antagonists, suggesting that the protective effects were not mediated through these receptors. Conjugation of JWH007 to a spacer (GA003) abolished activity in the guinea-pig ileum and the conjugation of JWH007 to a spacer and dendrimer (GA006) was found to be toxic in the macrophage assay. These studies show that cannabinoid-mediated inhibition of guinea-pig ileum contractions is not mediated through the CB1, CB2, CBe or GPR55 receptor. These receptors were not involved in the (+)WIN 55,212-2 mediated protection against hydrogen peroxide-induced damage in the ileum. The approach of attaching a dendrimer to JWH007 to prevent central nervous system (CNS) penetration does not appear to be a feasible approach because the cannabinoid-dendrimer was unexpectedly cytotoxic