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Research ArticleBEHAVIORAL PHARMACOLOGY

The Role of Several Kinases in Mice Tolerant to Δ9-Tetrahydrocannabinol

Matthew C. Lee, Forrest L. Smith, David L. Stevens and Sandra P. Welch
Journal of Pharmacology and Experimental Therapeutics May 2003, 305 (2) 593-599; DOI: https://doi.org/10.1124/jpet.102.044446
Matthew C. Lee
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Forrest L. Smith
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David L. Stevens
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Sandra P. Welch
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Abstract

It has been suggested that the cannabinoid receptor type 1 (CB1), a G protein-coupled receptor, is internalized after agonist binding and activation of the second messenger pathways. It is proposed that phosphorylation enhances the down-regulation of the CB1 receptor, thus contributing to tolerance. Alterations in phosphorylation of proteins in the signal transduction cascade after CB1receptor activation could also alter tolerance to cannabinoids. We addressed our hypothesis by evaluating the role of several kinases in antinociceptive tolerance to Δ9-tetrahydrocannabinol (THC). We evaluated cAMP-dependent protein kinase (PKA) using KT5720, a PKA inhibitor; protein kinase C (PKC) using bisindolylmaleimide I, HCl (bis), a PKC inhibitor; cGMP-dependent protein kinase (PKG) using KT5823, a PKG inhibitor; β-adrenergic receptor kinase (β-ARK) using low molecular weight heparin (LMWH), a β-ARK inhibitor; and phosphatidylinositol-3 kinase (PI3-K) using 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), a PI3-K inhibitor and PP1, a Src family tyrosine kinase inhibitor. The cAMP analog used was dibutyryl-cAMP and the cGMP analog used was dibutyryl-cGMP. Our data indicate that selective kinases may be involved in cannabinoid tolerance. Mice and rats were rendered tolerant to Δ9-THC. The PKG inhibitor KT5823, the β-ARK inhibitor LMWH, the PI3-K inhibitor LY294002, and inhibition of PKC by bis had no effect on tolerance. At a higher dose, bis attenuated the antinociceptive effect of Δ9-THC in nontolerant mice. PP1, the Src family tyrosine kinase inhibitor, and KT5720, the PKA inhibitor, reversed THC-induced tolerance. In addition, inhibition of PKA reversed a decrease in dynorphin release shown to accompany THC tolerance in rats. These data support a role for PKA and Src tyrosine kinase in phosphorylation events in Δ9-THC-tolerant mice.

Footnotes

  • This study was supported by the National Institute on Drug Abuse Grants DA05274 and KO2-DA00186, the National Institute on Drug Abuse Center for Drug Abuse Research, and 2PODA097789.

  • DOI: 10.1124/jpet.102.044446

  • Abbreviations:
    Δ9-THC
    Δ9-tetrahydrocannabinol
    CB
    cannabinoid receptor
    TK
    tyrosine kinase
    PKA
    cAMP-dependent protein kinase
    PKG
    cGMP-dependent protein kinase
    PKC
    protein kinase C
    MAPK
    mitogen-activated protein kinase
    GRK
    G protein-coupled receptor kinase
    β-ARK,β-adrenergic receptor kinase
    LMWH, low molecular weight heparin
    PI3-K
    phosphatidylinositol-3 kinase
    % MPE
    percentage of maximum possible effect
    DMSO
    dimethyl sulfoxide
    bis
    bisindolymaleimide
    dH2O
    distilled water
    db
    dibutyryl
    GPCR
    G protein-coupled receptor
    • Received September 17, 2002.
    • Accepted January 24, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 305 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 2
1 May 2003
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Research ArticleBEHAVIORAL PHARMACOLOGY

The Role of Several Kinases in Mice Tolerant to Δ9-Tetrahydrocannabinol

Matthew C. Lee, Forrest L. Smith, David L. Stevens and Sandra P. Welch
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 593-599; DOI: https://doi.org/10.1124/jpet.102.044446

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Research ArticleBEHAVIORAL PHARMACOLOGY

The Role of Several Kinases in Mice Tolerant to Δ9-Tetrahydrocannabinol

Matthew C. Lee, Forrest L. Smith, David L. Stevens and Sandra P. Welch
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 593-599; DOI: https://doi.org/10.1124/jpet.102.044446
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