Chronic oxycodone induces integrated stress response in rat brain.

Publisher: BioMed Central Country of Publication: England NLM ID: 100966986 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-2202 (Electronic) Linking ISSN: 14712202 NLM ISO Abbreviation: BMC Neurosci Subsets: MEDLINE

Original Publication: London: BioMed Central, [2000-

Analgesics, Opioid/*pharmacology ; Brain/*drug effects ; Brain/*metabolism ; Oxycodone/*pharmacology ; Stress, Physiological/*drug effects ; Stress, Physiological/*physiology; Activating Transcription Factor 4/metabolism ; Animals ; Brain/pathology ; Cell Line, Tumor ; Female ; HSP70 Heat-Shock Proteins/metabolism ; Heat-Shock Proteins/metabolism ; Humans ; Phosphorylation/drug effects ; RNA, Messenger/metabolism ; Rats, Sprague-Dawley ; Receptor, Platelet-Derived Growth Factor alpha/metabolism

Background: Oxycodone is an opioid that is prescribed to treat multiple types of pain, especially when other opioids are ineffective. Unfortunately, similar to other opioids, repetitive oxycodone administration has the potential to lead to development of analgesic tolerance, withdrawal, and addiction. Studies demonstrate that chronic opioid exposure, including oxycodone, alters gene expression profiles and that these changes contribute to opioid-induced analgesic effect, tolerance and dependence. However, very little is known about opioids altering the translational machinery of the central nervous system. Considering that opioids induce clinically significant levels of hypoxia, increase intracellular Ca(2+) levels, and induce the production of nitric oxide and extracellular glutamate transmission, we hypothesize that opioids also trigger a defensive mechanism called the integrated stress response (ISR). The key event in the ISR activation, regardless of the trigger, is phosphorylation of translation initiation factor 2 alpha (eIF2α), which modulates expression and translational activation of specific mRNAs important for adaptation to stress. To test this hypothesis, we used an animal model in which female rats were orally gavaged with 15 mg/kg of oxycodone every 24 h for 30 days.
Results: We demonstrated increased levels of hsp70 and BiP expression as well as phosphorylation of eIF2α in various rat brain areas after oxycodone administration. Polysomal analysis indicated oxycodone-induced translational stimulation of ATF4 and PDGFRα mRNAs, which have previously been shown to depend on the eIF2α kinase activation. Moreover, using breast adenocarcinoma MCF7 cells, which are known to express the μ-opioid receptor, we observed induction of the ISR pathway after one 24-h treatment with oxycodone.
Conclusions: The combined in vivo and in vitro data suggest that prolonged opioid treatment induces the integrated stress response in the central nervous system; it modulates translational machinery in favor of specific mRNA and this may contribute to the drug-induced changes in neuronal plasticity.

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R01 GM020818 United States GM NIGMS NIH HHS; 2R01GM20818 United States GM NIGMS NIH HHS

0 (Analgesics, Opioid)
0 (Atf4 protein, rat)
0 (GRP78 protein, rat)
0 (HSP70 Heat-Shock Proteins)
0 (Heat-Shock Proteins)
0 (RNA, Messenger)
145891-90-3 (Activating Transcription Factor 4)
CD35PMG570 (Oxycodone)
EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor alpha)

Date Created: 20150918 Date Completed: 20160324 Latest Revision: 20210309

20250114

PMC4574280

10.1186/s12868-015-0197-8

26377394