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  • Title: Effect of cyclo(Leu-Gly) on cyclic GMP-phosphodiesterase activity changes associated with development of tolerance to morphine-induced antinociception, catalepsy, respiratory depression and mydriasis.
    Author: Burton CK, Ho IK, Hoskins B.
    Journal: J Pharmacol Exp Ther; 1991 Sep; 258(3):871-6. PubMed ID: 1653844.
    Abstract:
    A biochemical basis for the development of tolerance to morphine has yet to be defined. Although a number of models have been proposed, none can account for complete tolerance to this drug. Previous studies in our laboratory indicated that the development of complete tolerance to certain morphine-induced behaviors (antinociception, catalepsy and respiratory depression) is associated with changes in the activity of some form(s) of phosphodiesterase with cyclic GMP as substrate (cGMP-PDE) activity in the brain areas that mediate these behaviors (periaqueductal gray, striatum and medulla). In the present study, experiments were performed in which Cyclo(Leu-Gly), a dipeptide that inhibits the development of tolerance to morphine, was administered daily (2 mg/kg) to morphine-naive rats, coadministered with morphine or coadministered with morphine to morphine-tolerant rats and the cGMP-PDE activity was measured. The development of tolerance to the effects was inhibited or reversed by administration of cyclo(Leu-Gly) and there were corresponding changes in cGMP-PDE activity in various brain regions. Differences in cGMP hydrolysis between brain regions from morphine-tolerant animals, tolerance-inhibited animals and tolerance-reversed animals strengthens the evidence for direct involvement of cGMP-PDE(s) in tolerance phenomena.
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