Chronic morphine induces up-regulation of the pro-apoptotic Fas receptor and down-regulation of the anti-apoptotic Bcl-2 oncoprotein in rat brain.
1. This study was designed to assess the influence of activation and blockade of the endogenous opioid system in the brain on two key proteins involved in the regulation of programmed cell death: the pro-apoptotic Fas receptor and the anti-apoptotic Bcl-2 oncoprotein. 2. The acute treatment of rats with the mu-opioid receptor agonist morphine (3-30 mg x kg(-1), i.p., 2 h) did not modify the immunodensity of Fas or Bcl-2 proteins in the cerebral cortex. Similarly, the acute treatment with low and high doses of the antagonist naloxone (1 and 100 mg x kg(-1), i.p., 2 h) did not alter Fas or Bcl-2 protein expression in brain cortex. These results discounted a tonic regulation through opioid receptors on Fas and Bcl-2 proteins in rat brain. 3. Chronic morphine (10-100 mg x kg(-1), 5 days, and 10 mg x kg(-1), 13 days) induced marked increases (47-123%) in the immunodensity of Fas receptor in the cerebral cortex. In contrast, chronic morphine (5 and 13 days) decreased the immunodensity of Bcl-2 protein (15-30%) in brain cortex. Chronic naloxone (10 mg x kg(-1), 13 days) did not alter the immunodensities of Fas and Bcl-2 proteins in the cerebral cortex. 4. The concurrent chronic treatment (13 days) of naloxone (10 mg x kg(-1)) and morphine (10 mg x kg(-1)) completely prevented the morphine-induced increase in Fas receptor and decrease in Bcl-2 protein immunoreactivities in the cerebral cortex. 5. The results indicate that morphine, through the sustained activation of opioid receptors, can promote abnormal programmed cell death by enhancing the expression of pro-apoptotic Fas receptor protein and damping the expression of anti-apoptotic Bcl-2 oncoprotein.
Boronat
M A
MA
Laboratory of Neuropharmacology, Associate Unit of the Institute Cajal/CSIC, Department of Biology, University of the Balearic Islands, Cra. Valldemossa Km 7.5, E-07071 Palma de Mallorca, Spain.
García-Fuster
M J
MJ
García-Sevilla
J A
JA
D000818:Animals; D017209:Apoptosis; D002540:Cerebral Cortex / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation; D004359:Drug Therapy, Combination; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D016900:Neurofilament Proteins / Q000737:chemistry / Q000378:metabolism*; D009293:Opioid-Related Disorders / Q000188:drug therapy / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism*
D009292:Narcotic Antagonists; D009294:Narcotics; D016900:Neurofilament Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D009270:Naloxone; D009020:Morphine