Central administration of morphine inhibits brain and liver ornithine decarboxylase activity in neonatal rats: involvement of transcription- and non-transcription-dependent mechanisms.
This study examined whether the developmental deficits usually observed in infants born to opiate addicted mothers could involve effects on ornithine decarboxylase, a growth-controlling enzyme. Intracerebroventricular (i.c.v.) injection of a single dose of morphine (2 microg) to 6-day-old rats markedly decreased basal brain and liver ornithine decarboxylase activity as well as the increases in hepatic ornithine decarboxylase activity produced by subcutaneously (s.c.) administered insulin, an important trophic hormone. Centrally applied morphine acts supraspinally to downregulate peripheral ornithine decarboxylase activity, since s.c. administration of the same dose as used i.c.v. decreased neither basal liver ornithine decarboxylase levels nor tissue responsiveness to insulin. This does not imply that the opiate is unable to affect ornithine decarboxylase when applied systemically. In fact, a robust inhibition of both basal and induced liver ornithine decarboxylase activity was obtained in rat pups given 20 microg of morphine s.c. This larger dose is able to trigger the hepatic ornithine decarboxylase effects presumably by stimulating opiate receptors located at central sites after crossing the blood-brain barrier and penetrating into the brain. Concomitant administration of naloxone plus morphine i.c.v. prevented morphine from downregulating ornithine decarboxylase activity, confirming the participation of supraspinal opioid receptors in morphine ornithine decarboxylase actions. Finally, as was the case for insulin induced stimulation of ornithine decarboxylase activity, i.c.v. injection of morphine markedly diminished insulin induced stimulation of hepatic ornithine decarboxylase mRNA accumulation. In turn, contrary to the inhibition of basal ornithine decarboxylase activity, morphine did not lower basal hepatic ornithine decarboxylase mRNA levels when given alone. Thus, CNS morphine can apparently suppress tissue ornithine decarboxylase expression through both transcriptional and posttranscriptional mechanisms. The evidence obtained suggest that postnatal exposure to opiate drugs might detrimentally affect development by altering normal tissue ornithine decarboxylase ontogeny.
Bartolome
J V
JV
Department of Pharmacology, Duke University, Durham, NC 27710, USA.
Alicke
B
B
Bartolome
M B
MB
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D015152:Blotting, Northern; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007276:Injections, Intraventricular; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D011061:Poly A / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000502:physiology
D000701:Analgesics, Opioid; D007004:Hypoglycemic Agents; D007328:Insulin; D065108:Ornithine Decarboxylase Inhibitors; D011061:Poly A; D012313:RNA; D009020:Morphine; D009955:Ornithine Decarboxylase