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Yüce, Birol (2005): Cannabinoid-1 Rezeptoren (CB1) beeinflussen die Motilität des Dünndarms von Maus und Ratte: Untersuchungen zum peristaltischen Reflex und Dünndarmtransit. Dissertation, LMU München: Medizinische Fakultät



Background: CB-1 receptors are involved in neurotransmission of the GI-tract and thus motility phenomena. The effect of intestinal propulsion might partially be due to CB-1 receptor mediated effects on neuronal circuits like the peristaltic reflex. Aim: Aim of the study was to further characterize the influence of CB-1 receptors on small intestinal motility by using antagonists and the agonists in established in vivo and in vitro models. Methods: Segments of isolated rat ileum were studied in a chambered organ bath. The reflex was initiated by electrical stimulation, force and timing of the ascending reflex pathways of the myenteric part of the peristaltic reflex (ARPPR) of ileum were recorded. Chambers were separated by a baffle, allowing the ileum to pass, separating the stimulation and recording sites. The intestinal transit was evaluated in vivo in CB-1 receptor knockout (CB-1 -/-) and wildtype mice. Additionally electrophysiological properties of neuromuscular interaction were evaluated using standard intracellular recording techniques in both genotypes. Results: CB-1 deficient mice displayed an 40% accelerated transit compared to control mice. When applied into the recording chamber AEA significantly inhibited the ARPPR in a concentration dependent manner (10-9M 2,3±3,7%; 10-8M:-1,0±4,6%; 10-7M: 3,8±7,1%; 10-6M:13,1±5,8%; 10-5M:32,7±7,8%) in a CB-1 sensitive manner. Neither AM251 nor AEA had an influence on the timing regardless the chamber it was applied. AM251 significantly stimulated the force of the ARPPR in concentration dependent manner (AM251: 10-8M:11,8±9,5%; 10-7M:23,7±10,0%; 10-6M: 29,4±11,5%; 10-5M: 49,9±9,4%) Resting membrane potentials and neuronally induced inhibitory junction potentials in CB-1 KO mice are unchanged compared to wildtype littermates, however, the electrophysiological slow waves are more sensitive to blockade of Ca2+ channels in CB-1 -/- mice. Conclusions: The results indicate that antagonism at the CB-1 receptors exhibited a strong enhancement of the ARPPR whereas agonism at the CB-1 receptor reduces the ARPPR. The concept holds true since in CB-1 -/- mice small intestinal transit is significantly increased, suggesting the CB-1 receptor as a promising target for the treatment of motility disorders.