title: Differential regulation of behavioral tolerance to WIN55,212-2 by GASP1.
abstract: Cannabinoid agonists have shown some promise clinically as analgesics, in particular for cancer pain, in which they have the additional benefit of decreasing nausea. However, as for most other drugs, the long-term use of cannabinoids is limited by the development of tolerance. Several molecular mechanisms have been proposed to explain drug tolerance, including receptor downregulation. The cannabinoid 1 (CB1) receptors can be downregulated in vitro through an interaction with the G-protein-coupled receptor-associated sorting protein1, GASP1, that targets CB1 receptors for degradation after their agonist-mediated endocytosis. To investigate whether GASP1-mediated postendocytic sorting of the CB1 receptor contributes to tolerance to cannabinoid drugs in vivo, we generated a mouse with a disruption of GASP1. In wild-type mice, repeated administration of the cannabinoid agonist WIN55,212-2 promoted downregulation of CB1 receptor levels and concomitant tolerance to the effects of drug on antinociception, motor incoordination, and locomotor hypoactivity. In contrast, GASP1 knockout mice did not develop tolerance to any of these effects and showed no significant receptor downregulation. Taken together, this study provides evidence that GASP1 regulates CB1 receptor downregulation in vivo, and that postendocytic receptor trafficking has a key role in the development of tolerance to WIN55,212-2.
authors.affiliation: Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, CA, USA.
authors.forename: Lene
authors.initials: L
authors.lastname: Martini
authors.forename: Dawn
authors.initials: D
authors.lastname: Thompson
authors.forename: Viktor
authors.initials: V
authors.lastname: Kharazia
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Whistler
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004361:Drug Tolerance / Q000502:physiology; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009281:Naphthalenes / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000700:Analgesics; D048588:Benzoxazines; D002186:Cannabinoids; D002352:Carrier Proteins; C479636:Gprasp1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone