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.
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.
Burton
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CK
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson.
Ho
I K
IK
Hoskins
B
B
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002375:Catalepsy / Q000139:chemically induced* / Q000201:enzymology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D003864:Depression, Chemical; D004361:Drug Tolerance; D006868:Hydrolysis / Q000187:drug effects; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism; D009020:Morphine / Q000633:toxicity*; D009043:Motor Activity / Q000187:drug effects; D015878:Mydriasis / Q000139:chemically induced* / Q000201:enzymology; D009479:Neuropeptides / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects*; D009802:Oculomotor Nerve / Q000187:drug effects / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010487:Periaqueductal Gray / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012137:Respiratory System / Q000187:drug effects*
D009479:Neuropeptides; D010456:Peptides, Cyclic; C021166:cyclo(leucylglycine); D009020:Morphine; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006152:Cyclic GMP