PMID- 36478740
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20221210
IS  - 2296-634X (Print)
IS  - 2296-634X (Electronic)
IS  - 2296-634X (Linking)
VI  - 10
DP  - 2022
TI  - Morphine-mediated release of astrocyte-derived extracellular vesicle miR-23a 
      induces loss of pericyte coverage at the blood-brain barrier: Implications for 
      neuroinflammation.
PG  - 984375
LID - 10.3389/fcell.2022.984375 [doi]
LID - 984375
AB  - Opioids such as morphine are the most potent and efficacious drugs currently 
      available for pain management. Paradoxically, opioids have also been implicated 
      in inducing neuroinflammation and associated neurocognitive decline. Pericytes, a 
      critical component of the neurovascular unit (NVU), are centrally positioned 
      between endothelial cells and astrocytes, maintaining function of the blood-brain 
      barrier (BBB) nd regulating neuroinflammation by controlling monocyte influx 
      under various pathological conditions. The role of pericytes in morphine-mediated 
      neuroinflammation however, has received less attention, especially in the context 
      of how pericytes crosstalk with other central nervous system (CNS) cells. The 
      current study was undertaken to examine the effect of miRNAs released from 
      morphine-stimulated human primary astrocyte-derived extracellular vesicles 
      (morphine-ADEVs) in mediating pericyte loss at the blood-brain barrier, leading, 
      in turn, to increased influx of peripheral monocytes. Our findings suggest that 
      the heterogeneous nuclear ribonucleoprotein complex A2/B1 (hnRNP A2/B1) plays 
      role in morphine-mediated upregulation and release of miR-23a in ADEVs, and 
      through action of morphine via mu opioid receptor.We further demonstrated that 
      miR-23a in morphine-ADEVs could be taken up by pericytes, resulting in 
      downregulation of PTEN expression, ultimately leading to increased pericyte 
      migration. Furthermore, both overexpression of PTEN and blocking the miR-23a 
      target site at PTEN 3UTR (by transfecting miR-23a-PTEN target protector), 
      attenuated morphine-ADEV-mediated pericyte migration. We also demonstrated that 
      in the microvessels isolated from morphine-administered mice, there were fewer 
      PDGFbetaR + pericytes co-localizing with CD31(+) brain endothelial cells compared 
      with those from saline mice. In line with these findings, we also observed 
      increased loss of pericytes and a concomitantly increased influx of monocytes in 
      the brains of morphine-administered pericyte-labeled NG2-DsRed mice compared with 
      saline mice. In conclusion, our findings indicate morphine-ADEVs mediated loss of 
      pericyte coverage at the brain endothelium, thereby increasing the influx of 
      peripheral monocytes in the central nervous system, leading to neuroinflammation.
CI  - Copyright (c) 2022 Liao, Niu, Hu and Buch.
FAU - Liao, Ke
AU  - Liao K
AD  - Department of Pharmacology and Experimental Neuroscience, University of Nebraska 
      Medical Center, Omaha, NE, United States.
AD  - Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United 
      States.
FAU - Niu, Fang
AU  - Niu F
AD  - Department of Pharmacology and Experimental Neuroscience, University of Nebraska 
      Medical Center, Omaha, NE, United States.
FAU - Hu, Guoku
AU  - Hu G
AD  - Department of Pharmacology and Experimental Neuroscience, University of Nebraska 
      Medical Center, Omaha, NE, United States.
FAU - Buch, Shilpa
AU  - Buch S
AD  - Department of Pharmacology and Experimental Neuroscience, University of Nebraska 
      Medical Center, Omaha, NE, United States.
LA  - eng
PT  - Journal Article
DEP - 20221121
PL  - Switzerland
TA  - Front Cell Dev Biol
JT  - Frontiers in cell and developmental biology
JID - 101630250
PMC - PMC9720401
OTO - NOTNLM
OT  - drug abuse
OT  - extracellular vesicles
OT  - miRNA
OT  - monocyte
OT  - neuroinflammation
OT  - pericyte
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/12/09 06:00
MHDA- 2022/12/09 06:01
PMCR- 2022/01/01
CRDT- 2022/12/08 13:20
PHST- 2022/07/04 00:00 [received]
PHST- 2022/11/07 00:00 [accepted]
PHST- 2022/12/08 13:20 [entrez]
PHST- 2022/12/09 06:00 [pubmed]
PHST- 2022/12/09 06:01 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 984375 [pii]
AID - 10.3389/fcell.2022.984375 [doi]
PST - epublish
SO  - Front Cell Dev Biol. 2022 Nov 21;10:984375. doi: 10.3389/fcell.2022.984375. 
      eCollection 2022.