Fentanyl activates hypoxia-inducible factor 1 in neuronal SH-SY5Y cells and mice under non-hypoxic conditions in a μ-opioid receptor-dependent manner
| Autor: | Kiichi Hirota, Takuhiko Wakamatsu, Takehiko Adachi, Shinichi Kai, Shun Kishimoto, Hiroshi Harada, Satoshi Takabuchi, Kengo Suzuki, Hiroki Daijo, Tomoharu Tanaka, Kazuhiko Fukuda |
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| Rok vydání: | 2010 |
| Předmět: |
Male
SH-SY5Y medicine.drug_class Receptors Opioid mu Cycloheximide Pharmacology Kidney Fentanyl Time Remifentanil chemistry.chemical_compound Mice Piperidines Opioid receptor Cell Line Tumor Gene expression medicine Animals Humans A549 cell Neurons Dose-Response Relationship Drug Morphine business.industry Protein Stability Brain Hypoxia-Inducible Factor 1 alpha Subunit chemistry Opioid Gene Expression Regulation Cell culture Hypoxia-Inducible Factor 1 business medicine.drug |
| Zdroj: | European journal of pharmacology. 667(1-3) |
| ISSN: | 1879-0712 |
| Popis: | Hypoxia-inducible factor 1 (HIF-1) is the main transcription factor responsible for hypoxia-induced gene expression. Perioperative drugs including anesthetics have been reported to affect HIF-1 activity. However, the effect of fentanyl on HIF-1 activity is not well documented. In this study, we investigated the effect of fentanyl and other opioids on HIF-1 activity in human SH-SY5Y neuroblastoma cells, hepatoma Hep3B cells, lung adenocarcinoma A549 cells and mice. Cells were exposed to fentanyl, and HIF-1 protein expression was examined by Western blot analysis using anti-HIF-1α and β antibodies. HIF-1-dependent gene expression was investigated by semi-quantitative real-time reverse transcriptase (RT)-PCR (qRT-PCR) and luciferase assay. Furthermore, fentanyl was administered intraperitoneally and HIF-1-dependent gene expression was investigated by qRT-PCR in the brains and kidneys of mice. A 10-μM concentration of fentanyl and other opioids, including 1 μM morphine and 4 μM remifentanil, induced HIF-1α protein expression and HIF-1 target gene expression in an opioid receptor-dependent manner in SH-SY5Y cells with activity peaking at 24h. Fentanyl did not augment HIF-1α expression during hypoxia-induced induction. HIF-1α stabilization assays and experiments with cycloheximide revealed that fentanyl increased translation from HIF-1α mRNA but did not stabilize the HIF-1α protein. Furthermore, fentanyl induced HIF-1 target gene expression in the brains of mice but not in their kidneys in a naloxone-sensitive manner. In this report, we describe for the first time that fentanyl, both in vitro and in vivo, induces HIF-1 activation under non-hypoxic conditions, leading to increases in expression of genes associated with adaptation to hypoxia. |
| Databáze: | OpenAIRE |
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