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Research ArticleBehavioral Pharmacology

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

Mary K. Piscura, Diana E. Sepulveda, Malabika Maulik, Josée Guindon, Angela N. Henderson-Redmond and Daniel J. Morgan
Journal of Pharmacology and Experimental Therapeutics April 2023, 385 (1) 17-34; DOI: https://doi.org/10.1124/jpet.122.001367
Mary K. Piscura
Department of Biomedical Sciences, Marshall University, Huntington, West Virginia (M.K.P., M.M., A.N.H.-R., D.J.M.); Department of Pharmacology (D.E.S.) and Graduate Program in Anatomy (M.K.P.), Penn State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmacology and Neuroscience (J.G.) and Center of Excellence for Translational Neuroscience and Therapeutics (J.G.), Texas Tech University Health Sciences Center, Lubbock, Texas
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Diana E. Sepulveda
Department of Biomedical Sciences, Marshall University, Huntington, West Virginia (M.K.P., M.M., A.N.H.-R., D.J.M.); Department of Pharmacology (D.E.S.) and Graduate Program in Anatomy (M.K.P.), Penn State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmacology and Neuroscience (J.G.) and Center of Excellence for Translational Neuroscience and Therapeutics (J.G.), Texas Tech University Health Sciences Center, Lubbock, Texas
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Malabika Maulik
Department of Biomedical Sciences, Marshall University, Huntington, West Virginia (M.K.P., M.M., A.N.H.-R., D.J.M.); Department of Pharmacology (D.E.S.) and Graduate Program in Anatomy (M.K.P.), Penn State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmacology and Neuroscience (J.G.) and Center of Excellence for Translational Neuroscience and Therapeutics (J.G.), Texas Tech University Health Sciences Center, Lubbock, Texas
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Josée Guindon
Department of Biomedical Sciences, Marshall University, Huntington, West Virginia (M.K.P., M.M., A.N.H.-R., D.J.M.); Department of Pharmacology (D.E.S.) and Graduate Program in Anatomy (M.K.P.), Penn State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmacology and Neuroscience (J.G.) and Center of Excellence for Translational Neuroscience and Therapeutics (J.G.), Texas Tech University Health Sciences Center, Lubbock, Texas
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Angela N. Henderson-Redmond
Department of Biomedical Sciences, Marshall University, Huntington, West Virginia (M.K.P., M.M., A.N.H.-R., D.J.M.); Department of Pharmacology (D.E.S.) and Graduate Program in Anatomy (M.K.P.), Penn State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmacology and Neuroscience (J.G.) and Center of Excellence for Translational Neuroscience and Therapeutics (J.G.), Texas Tech University Health Sciences Center, Lubbock, Texas
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Daniel J. Morgan
Department of Biomedical Sciences, Marshall University, Huntington, West Virginia (M.K.P., M.M., A.N.H.-R., D.J.M.); Department of Pharmacology (D.E.S.) and Graduate Program in Anatomy (M.K.P.), Penn State University College of Medicine, Hershey, Pennsylvania; and Department of Pharmacology and Neuroscience (J.G.) and Center of Excellence for Translational Neuroscience and Therapeutics (J.G.), Texas Tech University Health Sciences Center, Lubbock, Texas
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Abstract

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 β-arrestin2 scaffolding protein. Tolerance to cannabinoid drugs is reduced in S426A/S430A mutant mice and β-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 β-arrestin2. Therefore, we assessed acute response and tolerance to the cannabinoids delta-9-tetrahydrocannabinol (Δ9-THC) and CP55,940 in S426A/S430A x β-arrestin2 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 Δ9-THC. Female S426A/S430A single- and double-mutant mice were more sensitive to acute antinociception (CP55,940 and Δ9-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 β-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.

SIGNIFICANCE STATEMENT A better understanding of the molecular mechanisms involved in tolerance will improve the therapeutic potential of cannabinoid drugs. This study determined that further deletion of β-arrestin2 does not enhance the delay in cannabinoid tolerance observed in CB1R S426A/S430A mutant mice.

Footnotes

    • Received June 29, 2022.
    • Accepted January 10, 2023.
  • dx.doi.org/10.1124/jpet.122.001367.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 385 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 1
1 Apr 2023
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Research ArticleBehavioral Pharmacology

Role of Residues S426 and S430 in Cannabinoid Tolerance

Mary K. Piscura, Diana E. Sepulveda, Malabika Maulik, Josée Guindon, Angela N. Henderson-Redmond and Daniel J. Morgan
Journal of Pharmacology and Experimental Therapeutics April 1, 2023, 385 (1) 17-34; DOI: https://doi.org/10.1124/jpet.122.001367

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Research ArticleBehavioral Pharmacology

Role of Residues S426 and S430 in Cannabinoid Tolerance

Mary K. Piscura, Diana E. Sepulveda, Malabika Maulik, Josée Guindon, Angela N. Henderson-Redmond and Daniel J. Morgan
Journal of Pharmacology and Experimental Therapeutics April 1, 2023, 385 (1) 17-34; DOI: https://doi.org/10.1124/jpet.122.001367
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