The Impact of Morphine on the Characteristics and Function Properties of Human Mesenchymal Stem Cells
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Morphine is an analgesic drug therapeutically administered to relieve pain. However, this drug has numerous side effects, which include impaired healing and regeneration after injuries or tissue damages. It suggests negative effects of morphine on stem cells which are responsible for tissue regeneration. Therefore, we studied the impact of morphine on the properties and functional characteristics of human bone marrow-derived mesenchymal stem cells (MSCs). The presence of μ-, δ- and κ-opioid receptors (OR) in untreated MSCs, and the enhanced expression of OR in MSCs pretreated with proinflammatory cytokines, was demonstrated using immunoblotting and by flow cytometry. Morphine modified in a dose-dependent manner the MSC phenotype, inhibited MSC proliferation and altered the ability of MSCs to differentiate into adipocytes or osteoblasts. Furthermore, morphine rather enhanced the expression of genes for various immunoregulatory molecules in activated MSCs, but significantly inhibited the production of the vascular endothelial growth factor, hepatocyte growth factor or leukemia inhibitory factor. All of these observations are underlying the selective impact of morphine on stem cells, and offer an explanation for the mechanisms of the negative effects of opioid drugs on stem cells and regenerative processes after morphine administration or in opioid addicts.
KeywordsMesenchymal stem cells Morphine Opioid receptors Gene expression Growth factors Cytokines
This work was supported by grants from the Grant Agency of the Czech Republic no. 17-07070S and 17-05903S, the projects LO1309 and LO1508 from the Ministry of Education, Youth and Sports of the Czech Republic, institutional support of the Institute of Physiology (RVO:6798523) and by the project SVV 244-260435 from Charles University, Prague.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflicts of interest.
- 1.Barlass, U., Dutta, R., Cheema, H., George, J., Sareen, A., Dixit, A., Yuan, Z., Giri, B., Meng, J., Banerjee, S., Banerjee, S., Dudeja, V., Dawra, R. K., Roy, S., & Saluja, A. K. (2018). Morphine worsens the severity and prevents pancreatic regeneration in mouse models of acute pancreatitis. Gut, 67, 600–602.PubMedGoogle Scholar
- 3.Abdyazdani, N., Nourazarian, A., Nozad Charoudeh, H., Kazemi, M., Feizy, N., Akbarzade, M., Mehdizadeh, A., Rezaie, J., & Rahbarghazi, R. (2017). The role of morphine on rat neural stem cells viability, neuro-angiogenesis and neuro-steroidgenesis properties. Neuroscience Letters, 636, 205–212.CrossRefGoogle Scholar
- 5.Willner, D., Cohen-Yeshurun, A., Avidan, A., Ozersky, V., Shohami, E., & Leker, R. R. (2014). Short term morphine exposure in vitro alters proliferation and differentiation of neural progenitor cells and promotes apoptosis via mu receptors. PLoS One, 9(7), e103043. https://doi.org/10.1371/journal.pone.0103043.CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Holan, V., Trosan, P., Cejka, C., Javorkova, E., Zajicova, A., Hermankova, B., Chudickova, M., & Cejkova, J. (2015). A comparative study of the therapeutic potential of mesenchymal stem cells and limbal epithelial stem cells for ocular surface reconstruction. Stem Cells Translational Medicine, 4, 1052–1063.CrossRefGoogle Scholar
- 19.Hahn, J. W., Jagwani, S., Kim, E., Rendell, V. R., He, J., Ezerskiy, L. A., Wesselschmidt, R., Coscia, C. J., & Belcheva, M. M. (2010). Mu and kappa opioids modulate mouse embryonic stem cell-derived neural progenitor differentiation via MAP kinases. Journal of Neurochemistry, 112, 1431–1441.CrossRefGoogle Scholar
- 21.Ujcikova, H., Hlouskova, M., Cechova, K., Stolarova, K., Roubalova, L., & Svoboda, P. (2017). Determination of μ-, δ- and κ-opioid receptors in forebrain cortex of rats exposed to morphine for 10 days: Comparison with animals after 20 days of morphine withdrawal. PLoS One, 12(10), e0186797. https://doi.org/10.1371/journal.pone.0186797.CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Chiossone, L., Conte, R., Spaggiari, G. M., Serra, M., Romei, C., Bellora, F., Becchetti, F., Andaloro, A., Moretta, L., & Bottino, C. (2016). Mesenchymal stromal cells induce peculiar alternatively activated macrophages capable of dampening both innate and adaptive immune responses. Stem Cells, 34, 1909–1921.CrossRefGoogle Scholar
- 31.Yue, X., Wu, L. & Hu, W. (2015). The regulation of leukemia inhibitory factor. Cancer Cell Microenvironment, 2(3). Pii: e877.Google Scholar
- 33.Bortolotto, V., & Grilli, M. (2017). Opiate analgesics as negative modulators of adult hippocampal neurogenesis: Potential implications in clinical practice. Frontiers in Pharmacology, 8. https://doi.org/10.3389/fphar.2017.00254.