Cannabinoid Tolerance in S426A/S430A x b-Arrestin 2 Knockout Double-Mutant Mice

Mary K. Piscura, Diana E. Sepulveda, Malabika Maulik, Josee Guindon, Angela N. Henderson-Redmond, Daniel J. Morgan

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Tolerance to compounds that target G protein–coupled receptors (GPCRs), such as the cannabinoid type-1 receptor (CB1R), is in part facilitated by receptor desensitization. Processes that mediate CB1R desensitization include phosphorylation of CB1R residues S426 and S430 by a GPCR kinase and subsequent recruitment of the b-arrestin2 scaffolding protein. Tolerance to cannabinoid drugs is reduced in S426A/S430A mutant mice and b-arrestin2 knockout (KO) mice according to previous work in vivo. However, the presence of additional phosphorylatable residues on the CB1R C-terminus made it unclear as to whether recruitment to S426 and S430 accounted for all desensitization and tolerance by b-arrestin2. Therefore, we assessed acute response and tolerance to the cannabinoids delta-9-tetrahydrocannabinol (D9-THC) and CP55,940 in S426A/S430A x barrestin2 KO double-mutant mice. We observed both delayed tolerance and increased sensitivity to the antinociceptive and hypothermic effects of CP55,940 in male S426A/S430A single- and double-mutant mice compared with wild-type littermates, but not with D9-THC. Female S426A/S430A single- and double-mutant mice were more sensitive to acute antinociception (CP55,940 and D9-THC) and hypothermia (CP55,940 only) exclusively after chronic dosing and did not differ in the development of tolerance. These results indicate that phosphorylation of S426 and S430 are likely responsible for b-arrestin2–mediated desensitization as double-mutant mice did not differ from the S426A/S430A single-mutant model in respect to cannabinoid tolerance and sensitivity. We also found antinociceptive and hypothermic effects from cannabinoid treatment demonstrated by sex-, agonist-, and duration-dependent features.

Original languageEnglish
Pages (from-to)17-34
Number of pages18
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - 1 Apr 2023
Externally publishedYes


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