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 (CB 1 ) 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 CB 1 in spinal neurons ex vivo as well as in vivo. Importantly, uncoupling CB 1 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 CB 1 after agonist exposure in the nervous system and critically determines analgesic tolerance to cannabinoids.

Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ9-Tetrahydrocannabinol

“…This finding, coupled with the result that most striatum/BG nuclei did not exhibit desensitization or were altered only by the highest dose of THC, supports this hypothesis. Regional differences in CB 1 receptor down-regulation could be due to G-protein receptor-associated sorting protein (GASP), which promotes CB 1 receptor down-regulation by augmenting trafficking of the receptor to lysosomes for degradation (Tappe-Theodor et al, 2007). We have shown that CB 1 receptor down-regulation in the hippocampus and striatum is associated with loss of CB 1 protein (Sim-Selley et al, 2006), in agreement with a role for GASP in CB 1 receptor adaptation in the brain.…”

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

“…Finally, the receptor is either degraded in lysosomes or it is dephosphorylated (i.e., resensitized) and recycled to the cell membrane. Extensive studies on these processes led to the current concept that receptor internalization and rapid recycling prevent the development of tolerance (for review, see Waldhoer et al, 2004;Tappe-Theodor et al, 2007;Koch and Höllt, 2008;Busch-Dienstfertig and Stein, 2010) (Fig. 1).…”

Receptor-receptor interactions in heteroreceptor complexes: a new principle in biology. Focus on their role in learning and memory

“…Accordingly, GPCR internalization is strongly influenced by two of the above mentioned GIPs, the GRKs and arrestins [83]. However, other GIPs can regulate GPCR endocytic trafficking more selectively, for instance GASP which strongly promotes δ-OPR, D 2 R and CB1 trafficking to lysosomes after agonist-induced endocytosis [84][85][86] and SNX1 which binds the PAR1 receptor promoting its post-endocytic trafficking to lysosomes [87]. Overall, it is evident that GIPs play a role in every aspect of GPCR biology: biosynthetic trafficking, anchoring to the site of action, ligand binding, signalling and endocytosis.…”