title: A molecular basis of analgesic tolerance to cannabinoids.
abstract: Clinical usage of cannabinoids in chronic pain states is limited by their central side effects and the pharmacodynamic tolerance that sets in after repeated dosage. Analgesic tolerance to cannabinoids in vivo could be caused by agonist-induced downregulation and intracellular trafficking of cannabinoid receptors, but little is known about the molecular mechanisms involved. We show here that the type 1 cannabinoid receptor (CB1) interacts physically with G-protein-associated sorting protein 1 (GASP1), a protein that sorts receptors in lysosomal compartments destined for degradation. CB1-GASP1 interaction was observed to be required for agonist-induced downregulation of CB1 in spinal neurons ex vivo as well as in vivo. Importantly, uncoupling CB1 from GASP1 in mice in vivo abrogated tolerance toward cannabinoid-induced analgesia. These results suggest that GASP1 is a key regulator of the fate of CB1 after agonist exposure in the nervous system and critically determines analgesic tolerance to cannabinoids.
authors.affiliation: Pharmacology Institute, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Tappe-Theodor
authors.forename: Nitin
authors.initials: N
authors.lastname: Agarwal
authors.forename: István
authors.initials: I
authors.lastname: Katona
authors.forename: Tiziana
authors.initials: T
authors.lastname: Rubino
authors.forename: Lene
authors.initials: L
authors.lastname: Martini
authors.forename: Jakub
authors.initials: J
authors.lastname: Swiercz
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.forename: Hannah
authors.initials: H
authors.lastname: Monyer
authors.forename: Daniela
authors.initials: D
authors.lastname: Parolaro
authors.forename: Jennifer
authors.initials: J
authors.lastname: Whistler
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuner
authors.forename: Rohini
authors.initials: R
authors.lastname: Kuner
mesh_terms: D000700:Analgesics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002186:Cannabinoids / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004361:Drug Tolerance / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000700:Analgesics; D002186:Cannabinoids; D002352:Carrier Proteins; C479636:Gprasp1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D043884:Receptor, Cannabinoid, CB1