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Mitochondrial function and membrane integrity: an in vitro comparison between six commonly used opioids
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction: There is an ongoing opioid crisis in the United States where the illicit and non-medical use of prescription opioids is associated with an increasing number of overdose deaths. Few studies have investigated the effects of opioid-induced effects on cell viability, and comparative studies are scarce. Here we examine the toxic effect on cell viability from six commonly used opioids; methadone, morphine, oxycodone, hydromorphone, ketobemidone, and fentanyl with respect to mitochondrial and membrane function in vitro. Methods: The opioids were tested in four different cell cultures; primary cortical cell cultures, human neuroblastoma SH-SY5Y cells, and both differentiated and undifferentiated neuroblastoma/glioma hybrid NG108-15 cells. Results: The six different opioids displayed the same trend of reduced cell viability in all four cell cultures. The ranking of opioids, with respect to reduced cell viability were as follows; methadone, fentanyl, ketobemidone, oxycodone, hydromorphone, and morphine. Conclusion: Methadone was ranked as the most toxic opioid closely followed by fentanyl. Ketobemidone and oxycodone had modest effects while both hydromorphone and morphine only displayed little to no negative impact on cell viability.

Keywords [en]
Methadone, Morphine, Oxycodone, Hydromorphone, Ketobemidone, Fentanyl, Cell viability, primary cell cultures, NG108-15, SH-SY5Y, Opioids
National Category
Basic Medicine
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-393205OAI: oai:DiVA.org:uu-393205DiVA, id: diva2:1352091
Available from: 2019-09-17 Created: 2019-09-17 Last updated: 2019-10-04
In thesis
1. The effects of growth hormone on opioid-induced toxicity in vitro
Open this publication in new window or tab >>The effects of growth hormone on opioid-induced toxicity in vitro
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is an ongoing opioid crisis in the United States that is portrayed by a large number of opioid-related deaths. Many of these cases involve commonly used prescription opioids, such as morphine, oxycodone, fentanyl, and methadone. This is concerning and highlights the problems associated with long-term opioid treatment. In addition to opioid-related deaths, long-term opioid use may impact higher brain functions, such as cognitive function. The cause of cognitive decline following opioid treatment may be associated with increased neuronal cell death, inhibited neurogenesis, and altered volumes of specific brain regions important for cognition. Growth hormone (GH), a pituitary hormone regulated by the hypothalamic somatotropic axis, may counteract several of these effects. The hormone, alongside with its mediator insulin-like growth factor-1 (IGF-1), is associated with pro-cognitive effects and display promising neuroprotective actions in the CNS. The main aim for this thesis was to examine the impact of opioids on cell viability and the potentially protective, restorative, and effects linked to pro-cognitive properties of GH in mixed neuronal cell cultures and cell lines. The results clearly display that specific opioids, such as methadone, decrease cell viability, possibly via negative effects on mitochondrial morphology. GH treatment alleviated the negative effects of methadone in cortical cell cultures as well as successfully restored mitochondrial and membrane integrity past injury. Moreover, GH treatment to primary hippocampal cell cultures increased the number of dendritic spines, which are linked to higher cognitive functions, indicating that the hormone act as a cognitive enhancer in the CNS. In conclusion, this thesis provides further evidence that opioids negatively impact cell viability, an effect that may underlie reduced cognitive function as seen in several patients consuming opioids-long term. GH was able to counteract these effects and also able to restore damaged cellular functions. This thesis further confirms the essential role of GH in acting as a cognitive enhancer in the CNS, highlighting the potential role of GH as a treatment for cognitive dysfunctions.    

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 60
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 279
Keywords
Growth hormone, opioids, methadone, morphine, ketobemidone, fentanyl, oxycodone, hydromorphone, insulin-like growth factor, cell viability, NG108-15, SH-SY5Y, hippocampus, cortex
National Category
Cell and Molecular Biology Pharmaceutical Sciences Pharmacology and Toxicology
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-393940 (URN)978-91-513-0765-7 (ISBN)
Public defence
2019-11-22, B21, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2019-10-30 Created: 2019-10-04 Last updated: 2019-11-12

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Nylander, ErikKatila, LenkaZelleroth, SofiaNyberg, FredGröndbladh, AlfhildHallberg, M

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