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Extracellular vesicle-mediated delivery of anti-miR-106b inhibits morphine-induced primary ciliogenesis in the brain

Rong Ma1, Naseer A Kutchy2, Zhongbin Wang3

  • 1Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|April 4, 2023
PubMed

Insights

Extracellular vesicles (EVs) from morphine-exposed astrocytes drive primary ciliogenesis, a key factor in morphine tolerance. Inhibiting this process with anti-miR-106b delivered via EVs offers a potential therapeutic strategy for opioid use disorder.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Pharmacology

Background:

  • Opioid use disorder (OUD) arises from cellular changes in the brain due to repeated opioid use.
  • Extracellular vesicle (EV)-induced primary ciliogenesis is implicated in morphine tolerance.
  • Understanding the mechanisms of EV-mediated primary ciliogenesis is crucial for developing OUD treatments.

Purpose of the Study:

  • To investigate the mechanisms by which astrocyte-derived EVs mediate morphine-induced primary ciliogenesis.
  • To explore the therapeutic potential of targeting this pathway using EV-mediated delivery of small RNAs.

Main Methods:

  • Analysis of miRNA cargo in morphine-stimulated astrocyte-derived EVs (morphine-ADEVs).
  • Investigating the role of miR-106b and its target CEP97 in primary ciliogenesis.
  • Intranasal delivery of anti-miR-106b-loaded ADEVs in morphine-administered mice.
  • Confirmation of primary ciliogenesis in astrocytes from opioid abusers.

Main Results:

  • Morphine-ADEVs contain miRNA cargo that induces primary ciliogenesis in astrocytes.
  • miR-106b-5p within morphine-ADEVs targets CEP97, promoting primary ciliogenesis.
  • Intranasal delivery of anti-miR-106b-loaded ADEVs reduced miR-106b, inhibited ciliogenesis, and prevented morphine tolerance.
  • Primary ciliogenesis was observed in astrocytes of individuals with opioid abuse.

Conclusions:

  • miR-106b-5p in morphine-ADEVs mediates morphine-induced primary ciliogenesis by targeting CEP97.
  • EV-mediated delivery of anti-miR-106b is a promising therapeutic strategy to prevent morphine tolerance and OUD.
  • This study provides novel insights into primary cilium-mediated OUD mechanisms.
Keywords:
CEP97astrocyteciliogenesisexosomeextracellular vesicleintranasalmiR-106bmicroRNAmorphineprimary cilium

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