A molecular basis of analgesic tolerance to cannabinoids

Anke Tappe-Theodor, Nitin Agarwal, I. Katona, Tiziana Rubino, Lene Martini, Jakub Swiercz, Ken Mackie, Hannah Monyer, Daniela Parolaro, Jennifer Whistler, Thomas Kuner, Rohini Kuner

Research output: Contribution to journalArticle

77 Citations (Scopus)

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. CB 1-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.

Original languageEnglish
Pages (from-to)4165-4177
Number of pages13
JournalJournal of Neuroscience
Volume27
Issue number15
DOIs
Publication statusPublished - Apr 11 2007

Fingerprint

Cannabinoids
Analgesics
Protein Transport
GTP-Binding Proteins
Proteins
Down-Regulation
Cannabinoid Receptor CB1
Cannabinoid Receptors
Chronic Pain
Analgesia
Nervous System
Neurons

Keywords

  • Cannabinoid receptor 1
  • Endocytosis
  • GASP
  • Protein-protein interactions
  • Receptor trafficking
  • Spinal nociception

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Tappe-Theodor, A., Agarwal, N., Katona, I., Rubino, T., Martini, L., Swiercz, J., ... Kuner, R. (2007). A molecular basis of analgesic tolerance to cannabinoids. Journal of Neuroscience, 27(15), 4165-4177. https://doi.org/10.1523/JNEUROSCI.5648-06.2007

A molecular basis of analgesic tolerance to cannabinoids. / Tappe-Theodor, Anke; Agarwal, Nitin; Katona, I.; Rubino, Tiziana; Martini, Lene; Swiercz, Jakub; Mackie, Ken; Monyer, Hannah; Parolaro, Daniela; Whistler, Jennifer; Kuner, Thomas; Kuner, Rohini.

In: Journal of Neuroscience, Vol. 27, No. 15, 11.04.2007, p. 4165-4177.

Research output: Contribution to journalArticle

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 2007, 'A molecular basis of analgesic tolerance to cannabinoids', Journal of Neuroscience, vol. 27, no. 15, pp. 4165-4177. https://doi.org/10.1523/JNEUROSCI.5648-06.2007
Tappe-Theodor A, Agarwal N, Katona I, Rubino T, Martini L, Swiercz J et al. A molecular basis of analgesic tolerance to cannabinoids. Journal of Neuroscience. 2007 Apr 11;27(15):4165-4177. https://doi.org/10.1523/JNEUROSCI.5648-06.2007
Tappe-Theodor, Anke ; Agarwal, Nitin ; Katona, I. ; Rubino, Tiziana ; Martini, Lene ; Swiercz, Jakub ; Mackie, Ken ; Monyer, Hannah ; Parolaro, Daniela ; Whistler, Jennifer ; Kuner, Thomas ; Kuner, Rohini. / A molecular basis of analgesic tolerance to cannabinoids. In: Journal of Neuroscience. 2007 ; Vol. 27, No. 15. pp. 4165-4177.
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