Cannabinoid Tolerance Disruption in CB1R Mutant Mice Unable to Recruit Beta-Arrestin
Faculty Mentor Information
Dr. Daniel Morgan, Idaho State University
Presentation Date
7-16-2026
Abstract
Chronic pain represents an important medical problem with critical need for novel therapeutic approaches. Cannabinoids have promise as potential treatment for chronic pain in preclinical models. However, the development of tolerance and dependence are barriers to clinical use of cannabinoids. Cannabinoid tolerance involves phosphorylation of cannabinoid type 1 receptors (CB1R) by G Protein Receptor Kinases (GRKs) resulting in recruitment of beta-arestin proteins towards CB1R desensitization, internalization, and downregulation. This study uses a novel 8 point mutant (8PM) mouse where 8 putative GRK phosphorylation sites are mutated to alanine residues that can't be phosphorylated. Tolerance was assessed in wild-type, 8PM, and heterozygous mice by measuring the tail flick antinociception and hypothermia in mice treated once daily for 10 days with 0.3 mg/kg of CP55, 940. Our results show 8PM mice develop tolerance slower than WT counterparts with 8PM exhibiting a lack of tolerance to the antinociceptive effects of CP55,940 on days 3-5 and 8-10. Tolerance to hypothermic effects of CP55,940 were also disrupted in 8PM and heterozygous mice on days 3-10. Data shows effectiveness of the mutation in decreasing tolerance. These findings provide insight on the mechanism of cannabinoid tolerance and steps closer to its clinical efficacy.
Cannabinoid Tolerance Disruption in CB1R Mutant Mice Unable to Recruit Beta-Arrestin
Chronic pain represents an important medical problem with critical need for novel therapeutic approaches. Cannabinoids have promise as potential treatment for chronic pain in preclinical models. However, the development of tolerance and dependence are barriers to clinical use of cannabinoids. Cannabinoid tolerance involves phosphorylation of cannabinoid type 1 receptors (CB1R) by G Protein Receptor Kinases (GRKs) resulting in recruitment of beta-arestin proteins towards CB1R desensitization, internalization, and downregulation. This study uses a novel 8 point mutant (8PM) mouse where 8 putative GRK phosphorylation sites are mutated to alanine residues that can't be phosphorylated. Tolerance was assessed in wild-type, 8PM, and heterozygous mice by measuring the tail flick antinociception and hypothermia in mice treated once daily for 10 days with 0.3 mg/kg of CP55, 940. Our results show 8PM mice develop tolerance slower than WT counterparts with 8PM exhibiting a lack of tolerance to the antinociceptive effects of CP55,940 on days 3-5 and 8-10. Tolerance to hypothermic effects of CP55,940 were also disrupted in 8PM and heterozygous mice on days 3-10. Data shows effectiveness of the mutation in decreasing tolerance. These findings provide insight on the mechanism of cannabinoid tolerance and steps closer to its clinical efficacy.