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Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
Published on: July 29, 2014
Modulation of apoptosis in the mouse brain after morphine treatments and morphine withdrawal
Estela Pérez-San Emeterio1, Mónica Tramullas, María A Hurlé
1Departamento de Fisiología y Farmacología, Facultad de Medicina, Universidad de Cantabria, Santander, Spain.
Abstract:
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.
Insights
Chronic morphine use and withdrawal induce brain cell death by activating apoptosis pathways. Acute morphine, however, does not cause this neurotoxic effect.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Opioid analgesics like morphine are widely used for pain management.
- Understanding the long-term effects of morphine on brain health is crucial.
- Apoptosis, or programmed cell death, plays a role in neurological conditions.
Purpose of the Study:
- To investigate the impact of acute and chronic morphine administration and withdrawal on brain apoptotic cell death.
- To analyze the changes in apoptosis-regulating protein expression during morphine exposure and withdrawal.
Main Methods:
- Utilized TUNEL assay and active caspase-3 immunocytochemistry to detect apoptotic cells in mouse brains.
- Analyzed the expression levels of proapoptotic (FasL, Bad, Fas, t-Bid) and antiapoptotic (Bcl-2) proteins in cortical and hippocampal lysates.
- Examined effects of acute morphine, chronic morphine, and naltrexone-precipitated withdrawal.
Main Results:
- Acute morphine did not induce detectable apoptosis or alter caspase-3 activity.
- Chronic morphine and withdrawal led to scattered apoptotic neurons and astrocytes in the brain.
- Upregulation of proapoptotic proteins (FasL, Fas, Bad) and active caspases-8 and -3 was observed in chronic/withdrawn mice.
- Reduced expression of the antiapoptotic protein Bcl-2 was noted in abstinent mice.
Conclusions:
- Chronic morphine exposure and its withdrawal exert a neurotoxic effect on the brain.
- These effects are mediated by the activation of both intrinsic and extrinsic apoptotic pathways.
- Acute morphine administration does not appear to cause significant neurotoxicity via apoptosis.
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