A molecular basis of analgesic tolerance to cannabinoids

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

Research output: Contribution to journalArticlepeer-review

87 Scopus citations


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 (US)
Pages (from-to)4165-4177
Number of pages13
JournalJournal of Neuroscience
Issue number15
StatePublished - Apr 11 2007
Externally publishedYes


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

ASJC Scopus subject areas

  • Neuroscience(all)


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