Modulation of apoptosis in the mouse brain after morphine treatments and morphine withdrawal

We have examined the effects of acute or chronic morphine and naltrexone-precipitated withdrawal on mouse brain apoptotic cell death. The associated changes in the expression of apoptosis regulatory proteins were also analyzed. After a single dose of morphine, no apoptotic cells were detected by TUNEL or active caspase-3 immunocytochemistry. Concurrently, a down-regulation of the proapoptotic proteins FasL and Bad was detected in cortical lysates. On the other hand, the brains of chronic-morphine-treated mice and abstinent mice exhibited scattered apoptotic neurons and astrocytes throughout the brain. This neurotoxic effect was accompanied by up-regulation of the proapoptotic proteins FasL, Fas, and Bad and the active fragments of caspases-8 and -3 in cortical and hippocampal lysates. Abstinent mice also displayed a reduced expression of the antiapoptotic protein Bcl-2. No changes on t-Bid expression were detected under any experimental condition. These results suggest a neurotoxic effect exerted by chronic, but not acute, morphine and its withdrawal by activating both the intrinsic and the extrinsic apoptotic pathways. The possible clinical implications of our findings are discussed.