Cannabinoid type 1 receptor modulates intestinal propulsion by an attenuation of intestinal motor responses within the myenteric part of the peristaltic reflex B. YUECE, * A. SIBAEV, * U. C. BROEDL, * G. MARSICANO,  B. GO ¨ KE, * B. LUTZ,  H. D. ALLESCHERà & M. STORR*,§ *Department of Internal Medicine II and Institute of Surgical Research, Ludwig-Maximilians University Munich, Munich, Germany  Department of Physiological Chemistry, Johannes Gutenberg-University, Mainz, Germany àKlinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany §Department of Physiology and Biophysics, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada Abstract Cannabinoid-1 (CB1) receptor activation affects gastrointestinal propulsion in vivo. It was our aim to further characterize the involved myenteric mechanisms in vivo and in vitro. In CB1 )/) mice and wild-type littermates we performed in vivo transit experiments by charcoal feeding and in vitro electrophysiological recordings in mouse small intestinal smooth muscle. Ascending neuronal con- traction (ANC) following electrical field stimulation was studied in rat ileum in a partitioned organ bath separating the aboral stimulation site from the oral recording site. The knockout animals displayed an accelerated upper gastrointestinal transit compared to control animals. The CB1 receptor antagonist AM251 stimulated the force of the ANC in a con- centration dependent manner when added in the oral chamber. Anandamide significantly inhibited the ANC when added in the oral chamber. Neither AM251 nor anandamide had an influence on the contraction latency. No effects were observed when drugs were added in the aboral chamber, proving a CB1 mediated action on the neuromuscular junc- tion. Resting membrane potentials and neuronal induced inhibitory junction potentials in CB1 )/) mice were unchanged as compared to wild type. However, the electrophysiological slow waves were more sensitive to blockade of Ca 2+ channels in CB1 )/) mice. Our data strongly suggest a physiolo- gical involvement of the CB-1 receptor in the regu- lation of small intestinal motility. Therefore, CB1 receptors are a promising target for the treatment of motility disorders. Keywords anandamide, cannabinoid type 1 receptor, enteric nervous system, intestinal propulsion, peristaltic reflex. INTRODUCTION Cannabis sativa has a long recreational but also a medical history. Different preparations have been used for a variety of disorders. 1 Although some of these historically mentioned medical indications have to be questioned, there seems to be promising potential for cannabinoids, the active constituents of Cannabis sativa. Several years ago, an endogenous system for cannabinoids was identified, giving a functional basis for the effects of cannabinoids. This endocannabinoid system, which has been identified in various species, contains specific receptors, specific ligands and specific enzymes for synthesis and degradation of the endo- cannabinoids. 2 There are at least two established cannabinoid receptors, termed cannabinoid-1 (CB1) and CB2, with a discrepant distribution. Cannabi- noid-1 receptor is abundantly located on neuronal tissue of the central and peripheral nervous system, including the intestinal myenteric plexus, 3 but also on other tissues such as colonic epithelial cells. 4 In contrast, the CB2 receptor is mainly located on immune cells, 3 however recently CB2 receptors were reported on central neurons. 5 Several studies reported that CB1 mediated mechanisms affect motility of the Address for correspondence PD Dr Martin Storr, Department of Internal Medicine II, University of Munich, Marchioninistr. 15, 81377 Mu ¨ nchen, Germany. Tel: +49 89 7095 2281; fax: +49 89 7095 5281; e-mail: martin.storr@med.uni-muenchen.de Received: 24 April 2007 Accepted for publication: 25 May 2007 Neurogastroenterol Motil (2007) 19, 744–753 doi: 10.1111/j.1365-2982.2007.00975.x Ó 2007 The Authors Journal compilation Ó 2007 Blackwell Publishing Ltd 744