Inhibition of protein phosphatases alters the expression of morphine tolerance in mice.
Recently our laboratory found that tolerance to morphine-induced antinociception could be completely reversed with intracerebroventricular (i.c.v.) administration of a protein kinase A inhibitor, whereas intrathecal (i.t.) administration of the inhibitor produced hyperalgesia in morphine-tolerant mice. In the experiments described here, we sought to characterize further the role of phosphorylation events in supraspinal versus spinal opioid-mediated pain pathways and how such events might be involved in the development of antinociceptive tolerance. Two phosphatase inhibitors were administered centrally to determine whether they affected morphine-induced antinociception in naive or chronically morphine-treated mice. By the i.c.v. route, okadaic acid enhanced morphine-induced antinociception in tolerant mice and produced toxicity by the i.t. route. The calcineurin inhibitor ascomycin had no effect on antinociception following acute or chronic morphine treatment. These results suggest that increased activity of protein phosphatase types 1 and/or 2A in the brain may contribute to the development of morphine tolerance.
Bernstein
M A
MA
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0613, USA.
Welch
S P
SP
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004794:Enzyme Repression; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000494:pharmacology*; D019319:Okadaic Acid / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000187:drug effects; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors
D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D019319:Okadaic Acid; D009020:Morphine; D010749:Phosphoprotein Phosphatases