title: Anandamide transport inhibition by ARN272 attenuates nausea-induced behaviour in rats, and vomiting in shrews (Suncus murinus).
abstract: OBJECTIVE
  To understand how anandamide transport inhibition impacts the regulation of nausea and vomiting and the receptor level mechanism of action involved. In light of recent characterization of an anandamide transporter, fatty acid amide hydrolase-1-like anandamide transporter, to provide behavioural support for anandamide cellular reuptake as a facilitated transport process.
  
  
  METHODS
  The systemic administration of the anandamide transport inhibitor ARN272 ([(4-(5-(4-hydroxy-phenyl)-3,4-diaza-bicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-2-ylamino)-phenyl)-phenylamino-methanone]) was used to evaluate the prevention of LiCl-induced nausea-induced behaviour (conditioned gaping) in rats, and LiCl-induced emesis in shrews (Suncus murinus). The mechanism of how prolonging anandamide availability acts to regulate nausea in rats was explored by the antagonism of cannabinoid 1 (CB1) receptors with the systemic co-administration of SR141716.
  
  
  RESULTS
  The systemic administration of ARN272 produced a dose-dependent suppression of nausea-induced conditioned gaping in rats, and produced a dose-dependent reduction of vomiting in shrews. The systemic co-administration of SR141716 with ARN272 (at 3.0 mg·kg(-1)) in rats produced a complete reversal of ARN272-suppressed gaping at 1.0 mg·kg(-1). SR141716 alone did not differ from the vehicle solution.
  
  
  CONCLUSIONS
  These results suggest that anandamide transport inhibition by the compound ARN272 tonically activates CB1 receptors and as such produces a type of indirect agonism to regulate toxin-induced nausea and vomiting. The results also provide behavioural evidence in support of a facilitated transport mechanism used in the cellular reuptake of anandamide.
authors.affiliation: Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, Canada.
authors.forename: L D
authors.initials: LD
authors.lastname: O'Brien
authors.forename: C L
authors.initials: CL
authors.lastname: Limebeer
authors.forename: E M
authors.initials: EM
authors.lastname: Rock
authors.forename: G
authors.initials: G
authors.lastname: Bottegoni
authors.forename: D
authors.initials: D
authors.lastname: Piomelli
authors.forename: L A
authors.initials: LA
authors.lastname: Parker
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000932:Antiemetics / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects*; D001692:Biological Transport; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids / Q000378:metabolism*; D007527:Isoenzymes; D018021:Lithium Chloride; D008297:Male; D009325:Nausea / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control* / Q000523:psychology; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077285:Rimonabant; D012788:Shrews; D014839:Vomiting / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control* / Q000523:psychology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000932:Antiemetics; D001095:Arachidonic Acids; D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; D007527:Isoenzymes; D018021:Lithium Chloride; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant; D000099252:Fatty Acid Amide Hydrolases; C543264:Cnr1 protein, rat; C078814:anandamide
keywords: ARN272; CB1; FAAH-1-like anandamide transporter; FLAT; anandamide; endocannabinoid; gaping; nausea; taste reactivity; vomiting