key: cord-0015145-88mk6z2k
authors: Withey, Sarah L; Willis, Gareth R
title: Time to think small: Using extracellular vesicles to assess the effects of long-term opioid use
date: 2021-01-30
journal: EBioMedicine
DOI: 10.1016/j.ebiom.2021.103210
sha: 074490bd2b2f5c828ef4a7b47b8c74ad033ae742
doc_id: 15145
cord_uid: 88mk6z2k

nan

investigated the impact of in utero and postnatal oxycodone exposure on the miRNA signatures of brain-EVs and their association with neurodevelopment [7] . They found that oxycodone exposure modulates the microRNA cargo of brain-EVs, and that synaptodendritic damage to primary neurons is associated with impaired brain development. The role EVs play in oxycodone abuse is unclear, and to date, no study has characterized brain cell derived-EVs to understand the potential neurodegenerative effects of long-term oxycodone self-administration. There is a significant gap in knowledge regarding the role of EVs and their cargo in addiction pathology and neurodegeneration. Given the current opioid crisis, the need for novel blood-based tools to help decipher the dynamic molecular changes in the brain that are associated with opioid abuse is of paramount importance. Furthermore, understanding dynamic changes that occur at different stages of opioid abuse may aid the development of novel treatment interventions.

In a carefully executed study recently published in EBioMedicine, Kumar and coworkers [8] first used MRI to demonstrate that gray matter volume is lower in non-human primate subjects self-administering oxycodone compared to controls in brain regions associated with cognition and reward such as the frontal cortex, putamen and parietal cortex. Further, Kumar et al., demonstrated the presence of neurodegeneration-associated proteins and miRNAs in EVs isolated from plasma of subjects that self-administered oxycodone for approximately 3 years. The combination of these two minimally invasive methods offers a particular advantage to translating these findings to clinical populations. To our knowledge, the body of work by Kumar and colleagues is the first to provide evidence that the neurodegenerative effects caused by long-term oxycodone exposure could be assessed by studying the composition of subpopulations of brain cell-derived exosomes isolated from plasma. In turn, paving the way for the potential use of exosomes as a source of biomarkers to better predict the possible neurodegenerative and pro-inflammatory effects of opioid abuse.

Interestingly, the study also provided in vitro evidence to suggest that differential EV content is associated with altered functionality. Specifically, neuronal-derived EVs induce glucocorticoid receptor translocation to the nucleus and promote a pro-inflammatory response in monocytes in vitro. Taken together, EVs are likely just one component in a complex cascade of molecular biology that leads to opioid-associated neurotoxicity. By improving our understanding of EV biology and the role of EVs in opioid-associated neurodegeneration, in addition to providing prognostic/diagnostic value, EVs could emerge as a useful in vivo therapeutic target to inhibit disease propagation.

Further studies are required to understand the potential of EVs as biomarkers for opioid-associated neurodegeneration. When conducting future experiments, researchers should consider the following: How specific are the markers chosen to identify the EV source À are they unique to the parental cells, or absent in a subset of EVs? Are differences in EV cargo detectable at the serum level, thus mitigating the need for EV purification? A simplistic approach, that avoids substantial pre-analytical manipulation is more attractive, especially for clinical translation. What is the biodistribution of brain cell-derived EVs? What are the target cells of specific brain cell-derived EV subpopulations? How does acute versus chronic oxycodone use impact brain cell-derived EV release? Considering the vast heterogeneity in circulating EV populations, the pursuit for EV-associated protein profiles and miRNA signatures that are associated with neurodegeneration is challenging. Thus, carefully designed high-throughput EV characterization studies coupled with functional screening is likely required. Of particular note, in order to aid interstudy comparison and interpretation, it is imperative that, as the authors did in this study, researchers abide by the minimal information criteria for extracellular vesicle research (MISEV) which is set forth by the International Society of Extracellular Vesicles (ISEV) [9] . A diligent and careful approach should be taken when defining EV 'cargo'. Often, common EV isolation methods readily co-isolate non-EV material.

In conclusion, Kumar and colleagues present a thought-provoking approach to better understand the molecular and biological effects of oxycodone, and these findings may be applicable to other drugs of abuse pending further assessment. Brain cell-derived EVs following oxycodone self-administration may serve as a surrogate to predict the pathophysiological status of the host brain cells.

Signal of increased opioid overdose during COVID-19 from emergency medical services data

Alterations in brain structure and functional connectivity in prescription opioid-dependent patients

Predisposition to accelerated Alzheimer-related changes in the brains of human immunodeficiency virus negative opiate abusers

Hyperphosphorylated tau and amyloid precursor protein deposition is increased in the brains of young drug abusers

New insights into extracellular vesicle biogenesis and function

Role of extracellular vesicles in substance abuse and HIV-related neurological pathologies

Brain-derived extracellular vesicle microRNA signatures associated with in utero and postnatal oxycodone exposure

Brain cell-derived exosomes in plasma serve as neurodegeneration biomarkers in male cynomolgus monkeys selfadministrating oxycodone

Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines