@article{89089819197e47d4a34cc4d8a9d423d1,
title = "Extracellular vesicle-mediated delivery of anti-miR-106b inhibits morphine-induced primary ciliogenesis in the brain",
abstract = "Repeated use of opioids such as morphine causes changes in the shape and signal transduction pathways of various brain cells, including astrocytes and neurons, resulting in alterations in brain functioning and ultimately leading to opioid use disorder. We previously demonstrated that extracellular vesicle (EV)-induced primary ciliogenesis contributes to the development of morphine tolerance. Herein, we aimed to investigate the underlying mechanisms and potential EV-mediated therapeutic approach to inhibit morphine-mediated primary ciliogenesis. We demonstrated that miRNA cargo in morphine-stimulated-astrocyte-derived EVs (morphine-ADEVs) mediated morphine-induced primary ciliogenesis in astrocytes. CEP97 is a target of miR-106b and is a negative regulator of primary ciliogenesis. Intranasal delivery of ADEVs loaded with anti-miR-106b decreased the expression of miR-106b in astrocytes, inhibited primary ciliogenesis, and prevented the development of tolerance in morphine-administered mice. Furthermore, we confirmed primary ciliogenesis in the astrocytes of opioid abusers. miR-106b-5p in morphine-ADEVs induces primary ciliogenesis via targeting CEP97. Intranasal delivery of ADEVs loaded with anti-miR-106b ameliorates morphine-mediated primary ciliogenesis and prevents morphine tolerance. Our findings bring new insights into the mechanisms underlying primary cilium-mediated morphine tolerance and pave the way for developing ADEV-mediated small RNA delivery strategies for preventing substance use disorders.",
keywords = "astrocyte, CEP97, ciliogenesis, exosome, extracellular vesicle, intranasal, microRNA, miR-106b, morphine, primary cilium",
author = "Rong Ma and Kutchy, {Naseer A.} and Zhongbin Wang and Guoku Hu",
note = "Funding Information: This work was supported by startup funds from University of Nebraska Medical Center and the National Institutes of Health (NIH) grants R21DA046831 , R21DA042704 , R01DA043138 , and R01MH112848 . The project described was also supported by NIH grant 2P30MH062261 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH . We are grateful to Drs. Shilpa Buch and Ke Liao, and Mr. Shannon Callen for their outstanding technical assistance. We thank the Nebraska Center for Substance Abuse Research (NCSAR) for its support. We also thank Tom Bargar and Nicholas Conoan of the Electron Microscopy Core Facility (EMCF) at the University of Nebraska Medical Center for technical assistance. The EMCF is supported by state funds from the Nebraska Research Initiative (NRI) and the University of Nebraska Foundation, and institutionally by the Office of the Vice Chancellor for Research . Funding Information: This work was supported by startup funds from University of Nebraska Medical Center and the National Institutes of Health (NIH) grants R21DA046831, R21DA042704, R01DA043138, and R01MH112848. The project described was also supported by NIH grant 2P30MH062261. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We are grateful to Drs. Shilpa Buch and Ke Liao, and Mr. Shannon Callen for their outstanding technical assistance. We thank the Nebraska Center for Substance Abuse Research (NCSAR) for its support. We also thank Tom Bargar and Nicholas Conoan of the Electron Microscopy Core Facility (EMCF) at the University of Nebraska Medical Center for technical assistance. The EMCF is supported by state funds from the Nebraska Research Initiative (NRI) and the University of Nebraska Foundation, and institutionally by the Office of the Vice Chancellor for Research. R.M, N.K. Z.W. and G.H. designed and performed the experiments; collected, analyzed, and discussed the data; and drafted, revised and approved the final manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = may,
day = "3",
doi = "10.1016/j.ymthe.2023.03.030",
language = "English (US)",
volume = "31",
pages = "1332--1345",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "5",
}