QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, April 11, 2007, 27(15):4165-4177; doi:10.1523/JNEUROSCI.5648-06.2007

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (12) Citing Articles via Google Scholar Google Scholar Articles by Tappe-Theodor, A. Articles by Kuner, R. Search for Related Content PubMed PubMed Citation Articles by Tappe-Theodor, A. Articles by Kuner, R.

 Previous Article  |  Next Article 

Cellular/Molecular
A Molecular Basis of Analgesic Tolerance to Cannabinoids

Anke Tappe-Theodor,^1 * Nitin Agarwal,^1 * István Katona,² Tiziana Rubino,³ Lene Martini,⁴ Jakub Swiercz,¹ Ken Mackie,⁵ Hannah Monyer,⁶ Daniela Parolaro,³ Jennifer Whistler,⁴ Thomas Kuner,⁷ and Rohini Kuner¹

¹Pharmacology Institute, University of Heidelberg, 69120 Heidelberg, Germany, ²Institute of Experimental Medicine, Hungarian Academy of Sciences, 1083 Budapest, Hungary, ³Department of Structural and Functional Biology, Pharmacology Section and Neuroscience Center, University of Insubria, 21100 Busto Arsizio, Varese, Italy, ⁴Ernest Gallo Clinic and Research Center, University of California, San Francisco, San Francisco, California 94608, ⁵Department of Anesthesiology, University of Washington School of Medicine, Seattle, Washington 98195-6540, ⁶Department of Clinical Neurobiology, Interdisciplinary Center for Neuroscience, 69120 Heidelberg, Germany, and ⁷Max Planck Institute for Medical Research, 69120 Heidelberg, Germany

Correspondence should be addressed to Rohini Kuner, Pharmacology Institute, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. Email: rohini.kuner{at}pharma.uni-heidelberg.de

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.

Key words: cannabinoid receptor 1; receptor trafficking; protein–protein interactions; endocytosis; GASP; spinal nociception

---

Received Oct. 18, 2006; revised Feb. 1, 2007; accepted Feb. 5, 2007.

Correspondence should be addressed to Rohini Kuner, Pharmacology Institute, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. Email: rohini.kuner{at}pharma.uni-heidelberg.de

This article has been cited by other articles:

				D. L. McKinney, M. P. Cassidy, L. M. Collier, B. R. Martin, J. L. Wiley, D. E. Selley, and L. J. Sim-Selley Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to {Delta}9-Tetrahydrocannabinol J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 664 - 673. [Abstract] [Full Text] [PDF]

				D. Thompson, M. Pusch, and J. L. Whistler Changes in G Protein-coupled Receptor Sorting Protein Affinity Regulate Postendocytic Targeting of G Protein-coupled Receptors J. Biol. Chem., October 5, 2007; 282(40): 29178 - 29185. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help