Effects of serine/threonine protein phosphatase inhibitors on morphine-induced antinociception in the tail flick test in mice.
The aim of this study was to evaluate the effects of serine/threonine protein phosphatase (PP) inhibitors on morphine-induced antinociception in the tail flick test in mice, and on [3H]naloxone binding to the forebrain crude synaptosome fraction. Neither okadaic acid nor cantharidin (1-10000 nM) displaced [3H]naloxone from its specific binding sites, which indicates that they do not interact at the opioid receptor level. The i.c.v. administration of very low doses of okadaic acid (0.001-1 pg/mouse) and cantharidin (0.001-1 ng/mouse), which inhibit PP2A, produced a dose-dependent antagonism of the antinociception induced by morphine (s.c.). However, L-nor-okadaone (0.001 pg/mouse-1 ng/mouse, i.c.v.), an analogue of okadaic acid lacking activity against protein phosphatases, did not affect the antinociceptive effect of morphine. On the other hand, high doses of okadaic acid (10 ng/mouse, i.c.v.) and cantharidin (1 microg/mouse, i.c.v.), which also block PP1, and calyculin-A (0.1 fg/mouse-1 ng/mouse, i.c.v.), which inhibits equally both PP1 and PP2A, did not modify the morphine-induced antinociception. These results suggest that the activation of type 2A serine/threonine protein phosphatases may play a role in the antinociceptive effect of morphine, and that PP1 might counterbalace this activity.
Moncada
Ana
A
Department of Pharmacology and Neuroscience Institute, Medical School, University of Granada, Avenida de Madrid 11, 18012 Granada, Spain.
Cendán
Cruz Miguel
CM
Baeyens
José M
JM
Del Pozo
Esperanza
E
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002193:Cantharidin / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D007276:Injections, Intraventricular; D008387:Marine Toxins; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000378:metabolism / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects; D019319:Okadaic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D010080:Oxazoles / Q000494:pharmacology; D010146:Pain / Q000517:prevention & control; D010147:Pain Measurement / Q000379:methods; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D016548:Prosencephalon / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D014316:Tritium
D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D008387:Marine Toxins; D010080:Oxazoles; D014316:Tritium; D019319:Okadaic Acid; D009270:Naloxone; D009020:Morphine; C059041:calyculin A; D010749:Phosphoprotein Phosphatases; D002193:Cantharidin