Highlights
- •Spinal nerve ligation (SNL) altered circulating extracellular vesicular (EV) miRNAs.
- •Inflammatory-suppressing circulating-EV miRNAs were downregulated post-SNL.
- •The post-SNL circulating-EV miRNAs reflect changes in the injured L5 nerve.
- •Circulating-EV miRNAs regulate processes that contribute to nociception.
Abstract
Research into potentially novel biomarkers for chronic pain development is lacking.
microRNAs (miRNAs) are attractive candidates as biomarkers due to their conservation
across species, stability in liquid biopsies, and variation that corresponds to a
pathologic state. miRNAs can be sorted into extracellular vesicles (EVs) within the
cell and released from the site of injury. EVs transfer cargo molecules between cells
thus affecting key intercellular signaling pathways. The focus of this study was to
determine the plasma derived EV miRNA content in a chronic neuropathic pain rat model.
This was accomplished by performing either spinal nerve ligation (SNL; n = 6) or sham
(n = 6) surgery on anesthetized male Sprague-Dawley rats. Mechanosensitivity was assessed
and plasma derived EV RNA was isolated at baseline (BL), day 3, and 15 postnerve injury.
EV extracted small RNA was sequenced followed by differentially expressed (DE) miRNAs
and gene target enrichment/signaling pathway analysis performed using R packages and
TargetScan/Ingenuity pathway analysis (IPA), respectively. Seven of the DE miRNAs
were validated by Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR).
The data indicated that SNL rats displayed a time-dependent threshold reduction in
response to evoked stimuli from day 3 to day 15 postnerve injury. The data also revealed
that 22 and 74 miRNAs at day 3 and 15, respectively, and 33 miRNAs at both day 3 and
15 were uniquely DE between the SNL and sham groups. The key findings from this proposal
include (1) the majority of the DE EV miRNAs, which normally function to suppress
inflammation, were downregulated, and (2) several of the plasma derived DE EV miRNAs
reflect previously observed changes in the injured L5 nerve. The plasma derived DE
EV miRNAs regulate processes important in the development and maintenance of neuropathic
pain states and potentially serve as key regulators, biomarkers, and targets in the
progression and treatment of chronic neuropathic pain.
Perspective
This article describes the DE miRNA content of plasma derived EVs, comparing neuropathic
pain to normal conditions. This data indicates that EV miRNAs may be important in
nociception and may also serve as biomarkers for chronic pain. These results encourage
further research on EV miRNAs in chronic neuropathic pain sufferers.
Key words
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Article info
Publication history
Published online: June 19, 2019
Accepted:
May 24,
2019
Received in revised form:
May 9,
2019
Received:
November 30,
2018
Footnotes
Disclosure: The authors declare no competing financial interests.
Funding: This research was supported by Congressionally Directed Medical Research Programs- Applied Pain Research (MR157005C) because chronic pain is a serious issue for active and retired Service Members.
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SS is supported by the U. S. Army Research Laboratory and the U.S. Army Research Office under contract/grant number W911NF-13-1-0376 to The Geneva Foundation.Identification
Copyright
© Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc.
