title: Chronic oxycodone induces integrated stress response in rat brain.
abstract: 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.
authors.affiliation: Department of Emergency Medicine, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, USA. fan1@lsuhsc.edu.
authors.forename: Ruping
authors.initials: R
authors.lastname: Fan
authors.affiliation: Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, USA. lschro@lsuhsc.edu.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Schrott
authors.affiliation: University of Louisiana of Monroe, 700 University Ave., Monroe, LA, 71209, USA. stphnsnllng22@gmail.com.
authors.forename: Stephen
authors.initials: S
authors.lastname: Snelling
authors.affiliation: Department of Emergency Medicine, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, USA. jndi@lsuhsc.edu.
authors.forename: Julius
authors.initials: J
authors.lastname: Ndi
authors.affiliation: Department of Emergency Medicine, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, USA. tarnol@lsuhsc.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Arnold
authors.affiliation: Department of Emergency Medicine, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, USA. nkorne@lsuhsc.edu.|Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, USA. nkorne@lsuhsc.edu.
authors.forename: Nadejda L
authors.initials: NL
authors.lastname: Korneeva
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D010098:Oxycodone / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects* / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP
chemical_list: D051701:Activating Transcription Factor 4; D000701:Analgesics, Opioid; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D010098:Oxycodone; D012333:RNA, Messenger; D020796:Receptor, Platelet-Derived Growth Factor alpha; C497110:Atf4 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP