title: Functional role of high-affinity anandamide transport, as revealed by selective inhibition.
abstract: Anandamide, an endogenous ligand for central cannabinoid receptors, is released from neurons on depolarization and rapidly inactivated. Anandamide inactivation is not completely understood, but it may occur by transport into cells or by enzymatic hydrolysis. The compound N-(4-hydroxyphenyl)arachidonylamide (AM404) was shown to inhibit high-affinity anandamide accumulation in rat neurons and astrocytes in vitro, an indication that this accumulation resulted from carrier-mediated transport. Although AM404 did not activate cannabinoid receptors or inhibit anandamide hydrolysis, it enhanced receptor-mediated anandamide responses in vitro and in vivo. The data indicate that carrier-mediated transport may be essential for termination of the biological effects of anandamide, and may represent a potential drug target.
authors.affiliation: The Neurosciences Institute, 10640 J. J. Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: M
authors.initials: M
authors.lastname: Beltramo
authors.forename: N
authors.initials: N
authors.lastname: Stella
authors.forename: A
authors.initials: A
authors.lastname: Calignano
authors.forename: S Y
authors.initials: SY
authors.lastname: Lin
authors.forename: A
authors.initials: A
authors.lastname: Makriyannis
authors.forename: D
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D048588:Benzoxazines; D001692:Biological Transport / Q000187:drug effects; D001961:Bromcresol Green / Q000494:pharmacology; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D063388:Endocannabinoids; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000378:metabolism; D000077285:Rimonabant
chemical_list: D000700:Analgesics; D001095:Arachidonic Acids; D048588:Benzoxazines; D002186:Cannabinoids; D063388:Endocannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D005576:Colforsin; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D001961:Bromcresol Green; D000242:Cyclic AMP; D000077285:Rimonabant; C078814:anandamide; C107594:N-(4-hydroxyphenyl)arachidonylamide