Cannabinoids as potential new therapeutics of gastrointestinal motility and inflammatory disorders

Doctoral thesis English OPEN
Roberts, Leanne
  • Subject: RM
    mesheuropmc: lipids (amino acids, peptides, and proteins) | digestive, oral, and skin physiology

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.\ud \ud 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.\ud \ud These studies show that cannabinoid-mediated inhibition of guinea-pig ileum contractions is not mediated through the CB1, CB2, CBe or GPR55 receptor. These\ud receptors were not involved in the (+)WIN 55,212-2 mediated protection against\ud 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.
  • References (86)
    86 references, page 1 of 9

    Chapter 1: Introduction 1.1 Overview of thesis........................................................................ 2 1.2 Cannabis sativa............................................................................. 3 1.3 The endocannabinoid system....................................................... 4 1.4 Synthesis of endocannabinoids.................................................... 6 1.5 Endocannabinoid uptake mechanisms........................................ 7 1.6 Metabolism of endocannabinoids..................................................8 1.7 Cannabinoid pharmacology........................................................ 9 1.8 Cannabinoid receptor signalling pathways............................... 23 1.9 The therapeutic potential of cannabinoids in inflammatory bowel disease................................................................................. 27 1.10 Cannabinoid effects on intestinal inflammation and motility.. 32 1.11 Aims of thesis................................................................................ 45

    Chapter 2: General Methods 2.1 Introduction................................................................................... 47 2.2 Electrical field stimulation of the guinea-pig ileum.................... 48 2.3 Carbachol-induced contraction of the ileum............................... 52 xiii

    Chapter 3: Cannabinoid pharmacology of the guinea-pig ileum 3.1 Introduction..................................................................................... 63 3.2 Aims.................................................................................................. 73 3.3 Method.............................................................................................. 73 3.4 Results............................................................................................... 76 3.5 Discussion.......................................................................................... 103 MACCARRONE, M., VAN DER STELT, M., ROSSI, A., VELDINK, G.A., VLIEGENTHART, J.F. & AGRO, A.F. (1998) Anandamide hydrolysis by human cells in culture and brain. J Biol Chem, 273, 32332-32339.

    MAINGRET, F., PATEL, A.J., LAZDUNSKI, M. & HONORE, E. (2001) The endocannabinoid anandamide is a direct and selective blocker of the background K(+) channel TASK-1. EMBO J, 20, 47-54.

    MAKWANA, R., MOLLEMAN, A. & PARSONS, M.E. (2010a) Pharmacological characterization of cannabinoid receptor activity in the rat-isolated ileum myenteric plexus-longitudinal muscle preparation. Br J Pharmacol, 159, 1608- 1622.

    MAKWANA, R., MOLLEMAN, A. & PARSONS, M.E. (2010b) Evidence for both inverse agonism at the cannabinoid CB1 receptor and the lack of an endogenous cannabinoid tone in the rat and guinea-pig isolated ileum myenteric plexuslongitudinal muscle preparation. Br J Pharmacol, 160, 615-626.

    MANARA, L., CROCI, T., GUAGNINI, F., RINALDI-CARMONA, M., MAFFRAND, J.P., LE FUR, G., MUKENGE, S. & FERLA, G. (2002) Functional assessment of neuronal cannabinoid receptors in the muscular layers of human ileum and colon. Dig Liver Dis, 34, 262-269.

    MANG, C.F., ERBELDING, D. & KILBINGER, H. (2001) Differential effects of anandamide on acetylcholine release in the guinea-pig ileum mediated via vanilloid and non-CB1 cannabinoid receptors. Br J Pharmacol, 134, 161-167.

    MASSI, P., FUZIO, D., VIGANO, D., SACERDOTE, P. & PAROLARO, D. (2000) Relative involvement of cannabinoid CB(1) and CB(2) receptors in the Delta(9)- tetrahydrocannabinol-induced inhibition of natural killer activity. Eur J Pharmacol, 387, 343-347.

    MASSI, P., VACCANI, A., BIANCHESSI, S., COSTA, B., MACCHI, P. & PAROLARO, D. (2006a) The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells. Cell Mol Life Sci, 63(17), 2057-2066.

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