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 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 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 kg(-1), 5 days, and 10 mg 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 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 kg(-1)) and morphine (10 mg 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.