title: In vitro and non-invasive in vivo effects of the cannabinoid-1 receptor agonist AM841 on gastrointestinal motor function in the rat.
abstract: BACKGROUND
  Cannabinoids have been traditionally used for the treatment of gastrointestinal (GI) symptoms, but the associated central effects, through cannabinoid-1 receptors (CB1R), constitute an important drawback. Our aims were to characterize the effects of the recently developed highly potent long-acting megagonist AM841 on GI motor function and to determine its central effects in rats.
  
  
  METHODS
  Male Wistar rats were used for in vitro and in vivo studies. The effect of AM841 was tested on electrically induced twitch contractions of GI preparations (in vitro) and on GI motility measured radiographically after contrast administration (in vivo). Central effects of AM841 were evaluated using the cannabinoid tetrad. The non-selective cannabinoid agonist WIN 55,212-2 (WIN) was used for comparison. The CB1R (AM251) and CB2R (AM630) antagonists were used to characterize cannabinoid receptor-mediated effects of AM841.
  
  
  RESULTS
  AM841 dose-dependently reduced in vitro contractile activity of rat GI preparations via CB1R, but not CB2R or opioid receptors. In vivo, AM841 acutely and potently reduced gastric emptying and intestinal transit in a dose-dependent and AM251-sensitive manner. The in vivo GI effects of AM841 at 0.1 mg/kg were comparable to those induced by WIN at 5 mg/kg. However, at this dose, AM841 did not induce any sign of the cannabinoid tetrad, whereas WIN induced significant central effects.
  
  
  CONCLUSIONS
  The CB1R megagonist AM841 may potently depress GI motor function in the absence of central effects. This effect may be mediated peripherally and may be useful in the treatment of GI motility disorders.
authors.affiliation: Área de Farmacología y Nutrición y Unidad Asociada al Instituto de Química Médica (IQM) y al Centro de Investigación de Alimentos (CIAL) del Consejo Superior de Investigaciones Científicas (CSIC), Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain.|Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo multidisciplinar de investigación y tratamiento del dolor (i+DOL), Alcorcón, Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Abalo
authors.affiliation: MedizinischeKlinik 2 der Ludwig-Maximilians Universität München, Munich, Germany.|Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.affiliation: Área de Farmacología y Nutrición y Unidad Asociada al Instituto de Química Médica (IQM) y al Centro de Investigación de Alimentos (CIAL) del Consejo Superior de Investigaciones Científicas (CSIC), Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain.|Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo multidisciplinar de investigación y tratamiento del dolor (i+DOL), Alcorcón, Madrid, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Vera
authors.affiliation: MedizinischeKlinik 2 der Ludwig-Maximilians Universität München, Munich, Germany.|Department of Biochemistry, Medical University of Lodz, Lodz, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Fichna
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Thakur
authors.affiliation: Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo multidisciplinar de investigación y tratamiento del dolor (i+DOL), Alcorcón, Madrid, Spain.|Unidad del Dolor, Servicio de Anestesiología, Hospital General Universitario Gregorio Marañón (HGUGM), Madrid, Spain.
authors.forename: A E
authors.initials: AE
authors.lastname: López-Pérez
authors.affiliation: Center for Drug Discovery, Departments of Chemistry and Chemical Biology and Pharmaceutical Sciences, Northeastern Universtiy, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Makriyannis
authors.affiliation: Área de Farmacología y Nutrición y Unidad Asociada al Instituto de Química Médica (IQM) y al Centro de Investigación de Alimentos (CIAL) del Consejo Superior de Investigaciones Científicas (CSIC), Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain.|Grupo de Excelencia Investigadora URJC-Banco de Santander-Grupo multidisciplinar de investigación y tratamiento del dolor (i+DOL), Alcorcón, Madrid, Spain.
authors.forename: M I
authors.initials: MI
authors.lastname: Martín-Fontelles
authors.affiliation: MedizinischeKlinik 2 der Ludwig-Maximilians Universität München, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Storr
mesh_terms: D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D004195:Disease Models, Animal; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects*; D041981:Gastrointestinal Tract / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*
chemical_list: C507046:7'-Isothiocyanato-11-hydroxy-1',1'-dimethylheptylhexahydrocannabinol; D063386:Cannabinoid Receptor Agonists; C543264:Cnr1 protein, rat; D043884:Receptor, Cannabinoid, CB1; D013759:Dronabinol
keywords: AM841; cannabinoid; cannabinoid-1 receptor; gastrointestinal motility; pain; radiographic analysis