Home LiteratureArticle Details
PMID: 17428994 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

A molecular basis of analgesic tolerance to cannabinoids.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 27 ·No. 15 ·2007-04-11 ·Pages 4165-77

Tappe-Theodor A, Agarwal N, Katona I, Rubino T, Martini L, Swiercz J, Mackie K, Monyer H, Parolaro D, Whistler J, Kuner T, Kuner R

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.

MeSH Terms
Analgesics/metabolism,pharmacology Animals Cannabinoids/genetics,metabolism,pharmacology Carrier Proteins/genetics,metabolism Cell Line Drug Tolerance/physiology Humans Intracellular Signaling Peptides and Proteins Mice Rats Rats, Wistar Receptor, Cannabinoid, CB1/genetics,metabolism
Chemicals
Analgesics Cannabinoids Carrier Proteins Gprasp1 protein, mouse Intracellular Signaling Peptides and Proteins Receptor, Cannabinoid, CB1
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Tappe-Theodor Anke
Pharmacology Institute, University of Heidelberg, 69120 Heidelberg, Germany.
Agarwal Nitin
Katona István
Rubino Tiziana
Martini Lene
Swiercz Jakub
Mackie Ken
Monyer Hannah
Parolaro Daniela
Whistler Jennifer
Kuner Thomas
Kuner Rohini
References (45)
45 references, click to expand
  1. Distinct domains of the CB1 cannabinoid receptor mediate desensitization and internalization.
    J Neurosci. 1999 May 15;19(10):3773-80 PMID: 10234009
  2. Internalization and recycling of the CB1 cannabinoid receptor.
    J Neurochem. 1999 Aug;73(2):493-501 PMID: 10428044
  3. Downregulation of G protein-coupled receptors.
    Curr Opin Neurobiol. 2000 Jun;10(3):365-9 PMID: 10851176
  4. Agonist-induced internalization and trafficking of cannabinoid CB1 receptors in hippocampal neurons.
    J Neurosci. 2001 Apr 1;21(7):2425-33 PMID: 11264316
  5. Cannabinoids and pain.
    Curr Opin Investig Drugs. 2001 Mar;2(3):399-414 PMID: 11575713
  6. Regulation of opioid receptor trafficking and morphine tolerance by receptor oligomerization.
    Cell. 2002 Jan 25;108(2):271-82 PMID: 11832216
  7. Pre- and postsynaptic localizations of the CB1 cannabinoid receptor in the dorsal horn of the rat spinal cord.
    Neuroscience. 2002;110(4):755-64 PMID: 11934482
  8. Immunological aspects of recombinant adeno-associated virus delivery to the mammalian brain.
    J Virol. 2002 Aug;76(16):8446-54 PMID: 12134047
  9. Modulation of postendocytic sorting of G protein-coupled receptors.
    Science. 2002 Jul 26;297(5581):615-20 PMID: 12142540
  10. Development and optimization of adeno-associated virus vector transfer into the central nervous system.
    Methods Mol Med. 2003;76:221-36 PMID: 12526166
  11. Cellular mechanisms of Delta 9-tetrahydrocannabinol behavioural sensitization.
    Eur J Neurosci. 2003 Jan;17(2):325-30 PMID: 12542669
  12. The role of several kinases in mice tolerant to delta 9-tetrahydrocannabinol.
    J Pharmacol Exp Ther. 2003 May;305(2):593-9 PMID: 12606657
  13. Cannabis and the brain.
    Brain. 2003 Jun;126(Pt 6):1252-70 PMID: 12764049
  14. Helper virus-free, optically controllable, and two-plasmid-based production of adeno-associated virus vectors of serotypes 1 to 6.
    Mol Ther. 2003 Jun;7(6):839-50 PMID: 12788658
  15. Spinal upregulation of the nitric oxide synthase-interacting protein NOSIP in a rat model of inflammatory pain.
    Neurosci Lett. 2003 Oct 16;350(1):13-6 PMID: 12962906
  16. Mechanisms regulating membrane trafficking of G protein-coupled receptors in the endocytic pathway.
    Life Sci. 2003 Dec 5;74(2-3):217-24 PMID: 14607249
  17. Behavioral effects of cannabinoids show differential sensitivity to cannabinoid receptor blockade and tolerance development.
    Behav Pharmacol. 2004 Feb;15(1):1-12 PMID: 15075621
  18. Identification of a novel family of G protein-coupled receptor associated sorting proteins.
    J Neurochem. 2004 May;89(3):766-75 PMID: 15086532
  19. Signaling pathways involved in the development of cannabinoid tolerance.
    Trends Pharmacol Sci. 2004 Jun;25(6):325-30 PMID: 15165748
  20. Constitutive endocytic cycle of the CB1 cannabinoid receptor.
    J Biol Chem. 2004 Aug 20;279(34):36013-21 PMID: 15210689
  21. Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2.
    J Cell Biol. 2004 Jun 21;165(6):869-80 PMID: 15210733
  22. Reversal of delta 9-tetrahydrocannabinol-induced tolerance by specific kinase inhibitors.
    Eur J Pharmacol. 2004 Aug 2;496(1-3):99-108 PMID: 15288581
  23. PDZ domain proteins of synapses.
    Nat Rev Neurosci. 2004 Oct;5(10):771-81 PMID: 15378037
  24. A library of 7TM receptor C-terminal tails. Interactions with the proposed post-endocytic sorting proteins ERM-binding phosphoprotein 50 (EBP50), N-ethylmaleimide-sensitive factor (NSF), sorting nexin 1 (SNX1), and G protein-coupled receptor-associated sorting protein (GASP).
    J Biol Chem. 2004 Dec 24;279(52):54291-303 PMID: 15452121
  25. Targeted in vivo expression of proteins in the calyx of Held.
    Pflugers Arch. 2004 Dec;449(3):319-33 PMID: 15452710
  26. The AMPA receptor subunits GluR-A and GluR-B reciprocally modulate spinal synaptic plasticity and inflammatory pain.
    Neuron. 2004 Nov 18;44(4):637-50 PMID: 15541312
  27. Opioid tolerance and dependence -- do they matter?
    Eur J Pain. 2005 Apr;9(2):157-62 PMID: 15737807
  28. Ras/ERK signalling in cannabinoid tolerance: from behaviour to cellular aspects.
    J Neurochem. 2005 May;93(4):984-91 PMID: 15857401
  29. Cannabinoid tolerance and dependence: a review of studies in laboratory animals.
    Pharmacol Biochem Behav. 2005 Jun;81(2):300-18 PMID: 15919107
  30. Dopamine responsiveness is regulated by targeted sorting of D2 receptors.
    Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11521-6 PMID: 16049099
  31. Cannabinoid receptors as therapeutic targets.
    Annu Rev Pharmacol Toxicol. 2006;46:101-22 PMID: 16402900
  32. Constitutive activation drives compartment-selective endocytosis and axonal targeting of type 1 cannabinoid receptors.
    J Neurosci. 2006 Mar 22;26(12):3141-53 PMID: 16554465
  33. Cannabinoid mechanisms of pain suppression.
    Handb Exp Pharmacol. 2005;(168):509-54 PMID: 16596786
  34. Cannabinoid tolerance and dependence.
    Handb Exp Pharmacol. 2005;(168):691-717 PMID: 16596793
  35. Synaptic scaffolding protein Homer1a protects against chronic inflammatory pain.
    Nat Med. 2006 Jun;12(6):677-81 PMID: 16715092
  36. Neuromodulatory functions of the endocannabinoid system.
    J Endocrinol Invest. 2006;29(3 Suppl):27-46 PMID: 16751707
  37. Complexing receptor pharmacology: modulation of family B G protein-coupled receptor function by RAMPs.
    Ann N Y Acad Sci. 2006 Jul;1070:90-104 PMID: 16888151
  38. An essential role for constitutive endocytosis, but not activity, in the axonal targeting of the CB1 cannabinoid receptor.
    Mol Pharmacol. 2007 Apr;71(4):976-84 PMID: 17182888
  39. Fluoride-resistant acid phosphatase-containing neurones in dorsal root ganglia are separate from those containing substance P or somatostatin.
    Neuroscience. 1982 Jan;7(1):89-97 PMID: 6176904
  40. Clinical relevance of cannabis tolerance and dependence.
    J Clin Pharmacol. 1981 Aug-Sep;21(S1):143S-152S PMID: 6271820
  41. An amino-terminal variant of the central cannabinoid receptor resulting from alternative splicing.
    J Biol Chem. 1995 Feb 24;270(8):3726-31 PMID: 7876112
  42. Characterization of the role of spinal N-methyl-D-aspartate receptors in thermal nociception in the rat.
    Neuroscience. 1993 Nov;57(2):385-95 PMID: 7906873
  43. Tolerance and dependence to opiates.
    Acta Anaesthesiol Scand. 1997 Jan;41(1 Pt 2):184-6 PMID: 9061104
  44. Control of pain initiation by endogenous cannabinoids.
    Nature. 1998 Jul 16;394(6690):277-81 PMID: 9685157
  45. Termination of signaling by protease-activated receptor-1 is linked to lysosomal sorting.
    Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13698-702 PMID: 9811863
Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.5648-06.2007
Published
2007-04-11
Pages
4165-77
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6672554
Subset
IM
Grants
NIDA NIH HHS · K02 DA000286 · United States
NIDA NIH HHS · R01 DA011322 · United States
NIDA NIH HHS · DA00286 · United States
NIDA NIH HHS · DA11322 · United States
External Links
PubMed source DOI: 10.1523/JNEUROSCI.5648-06.2007 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2