Chronic oxycodone induces integrated stress response in rat brain

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Oxycodone, an opioid analgesic, can lead to tolerance, withdrawal, and addiction with chronic use.
• Opioid exposure alters gene expression, but effects on the central nervous system's translational machinery are poorly understood.
• Opioids may trigger the integrated stress response (ISR), a cellular defense mechanism involving eIF2α phosphorylation.

Purpose of the Study:

• To investigate if prolonged oxycodone administration activates the integrated stress response (ISR) in the rat central nervous system.
• To determine if oxycodone affects the translational machinery of neurons.
• To examine ISR induction in vitro using human breast adenocarcinoma cells expressing μ-opioid receptors.

Main Methods:

• Female rats were administered 15 mg/kg oxycodone orally daily for 30 days.
• Levels of hsp70, BiP, and phosphorylated eIF2α were measured in rat brain regions.
• Polysomal analysis assessed the translation of specific mRNAs (ATF4, PDGFRα).
• MCF7 cells were treated with oxycodone for 24 hours to assess ISR activation.

Main Results:

• Oxycodone administration increased hsp70 and BiP expression and eIF2α phosphorylation in rat brain areas.
• Oxycodone stimulated the translation of ATF4 and PDGFRα mRNAs, dependent on eIF2α kinase.
• In vitro, oxycodone treatment induced the ISR pathway in MCF7 cells.

Conclusions:

• Prolonged oxycodone treatment activates the integrated stress response (ISR) in the central nervous system.
• The ISR modulates the translational machinery, favoring specific mRNAs.
• These changes may contribute to opioid-induced alterations in neuronal plasticity and drug effects.