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Dissertation
The role of serum-derived small extracellular vesicles in pain
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2022
DOI:
https://doi.org/10.17918/00001164
Abstract
Chronic pain is a significant public health issue. Current treatments have limited efficacy and significant side effects, warranting research on alternative strategies for pain management. One approach involves using small extracellular vesicles (sEVs) to transport beneficial biomolecular cargo to aid pain resolution. We hypothesized that sEVs could impact the development of pain hypersensitivity in recipient mice. We investigated the role of serum-derived sEVs isolated from naïve or spared nerve injury (SNI) model mice. Dose response studies in naïve recipient mice show intrathecal injection of sEVs 1) transiently increased basal mechanical thresholds, 2) accelerated recovery from complete Freund's adjuvant induced inflammatory pain, and 3) delayed the development of neuropathic pain in SNI model mice. LC-MS-MS studies showed sEVs contained endogenous opioid peptides leu-enkephalin and nociceptin. Transient analgesia induced by sEVs was reversed by the opioid antagonist naltrexone, suggesting that leu-enkephalin in sEVs contributes to a short-term analgesic effect. miRNA profiling of sEVs from naïve and SNI model mice showed unique and overlapping signatures. miR-339-3p was one of the highly expressed miRNAs in both sEVs. We confirmed miR-339-3p can downregulate annexin A3 (ANXA3), a protein upregulated by microglia in neuropathic pain models. Uptake of sEVs decreased ANXA3 leading to inhibition of NF-kB activity suggesting miR-339-3p-ANXA3-NFkB axis could help attenuate pain and inflammation. Further, when cortical neuron-glia microelectrode array cultures were treated with sEVs, we observed reduced synchronous network activity demonstrating a modulatory role for sEVs in neuronal networks. Collectively, these studies demonstrate multiple mechanisms by which sEVs can attenuate pain.
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Details
- Title
- The role of serum-derived small extracellular vesicles in pain
- Creators
- Zhucheng Lin
- Contributors
- Seena Ajit (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 132 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991018097208504721