title: Pharmacological characterization of the peripheral FAAH inhibitor URB937 in female rodents: interaction with the Abcg2 transporter in the blood-placenta barrier.
abstract: OBJECTIVE
  URB937 is a peripherally restricted inhibitor of the anandamide-deactivating enzyme fatty-acid amide hydrolase (FAAH). Despite its limited access to the CNS, URB937 produces marked antinociceptive effects in rodents. URB937 is actively extruded from the CNS by the ATP-binding cassette (ABC) membrane transporter, Abcg2. Tissue Abcg2 levels are markedly different between males and females, and this transporter is known to limit the access of xenobiotics to the fetoplacental unit in gestating female rodents. In the present study, we investigated the tissue distribution and antinociceptive properties of URB937 in female mice and rats.
  
  
  METHODS
  We studied the systemic disposition of URB937 in female mice and the antinociceptive effects of this compound in models of visceral (acetic acid-induced writhing) and inflammatory nociception (carrageenan-induced hyperalgesia) in female mice and rats. Furthermore, we evaluated the interaction of URB937 with the blood-placenta barrier in gestating mice and rats.
  
  
  RESULTS
  Abcg2 restricted the access of URB937 to the CNS of female mice and rats. Nevertheless, URB937 produced a high degree of antinociception in female mice and rats in models of visceral and inflammatory pain. Moreover, the compound displayed a restricted access to placental and fetal tissues in pregnant mice and rats.
  
  
  CONCLUSIONS
  Peripheral FAAH blockade with URB937 reduces nociception in female mice and rats, as previously shown for males of the same species. In female mice and rats, Abcg2 limits the access of URB937, not only to the CNS, but also to the fetoplacental unit. LINKED ARTICLES This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8.
authors: Departments of Pharmacology and Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
authors: G
authors: G
authors: Moreno-Sanz
authors: O
authors: O
authors: Sasso
authors: A
authors: A
authors: Guijarro
authors: O
authors: O
authors: Oluyemi
authors: R
authors: R
authors: Bertorelli
authors: A
authors: A
authors: Reggiani
authors: D
authors: D
authors: Piomelli
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D019342:Acetic Acid; D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology* / Q000627:therapeutic use; D002351:Carrageenan; D063388:Endocannabinoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D010920:Placenta / Q000378:metabolism*; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012727:Sex Characteristics; D014018:Tissue Distribution; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D019342:Acetic Acid; D000581:Amidohydrolases; D000700:Analgesics; D001095:Arachidonic Acids; D002186:Cannabinoids; D002351:Carrageenan; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C501412:Abcg2 protein, mouse; C489249:Abcg2 protein, rat; C552918:URB937; C078814:anandamide