Highlights
- •The biochemical pathways related to oxylipins were outlined.
- •Genes encoding oxylipin related enzymes are expressed in the pain-circuit.
- •Gene expression and oxylipin concentrations were modified by inflammation.
- •Oxylipin injections evoked thermal nociceptive hypersensitivity in rats.
Abstract
Oxylipins are lipid peroxidation products that participate in nociceptive, inflammatory,
and vascular responses to injury. Effects of oxylipins depend on tissue-specific differences
in accumulation of precursor polyunsaturated fatty acids and the expression of specific
enzymes to transform the precursors. The study of oxylipins in nociception has presented
technical challenges leading to critical knowledge gaps in the way these molecules
operate in nociception. We applied a systems-based approach to characterize oxylipin
precursor fatty acids, and expression of genes coding for proteins involved in biosynthesis,
transport, signaling and inactivation of pro- and antinociceptive oxylipins in pain
circuit tissues. We further linked these pathways to nociception by demonstrating
intraplantar carrageenan injection induced gene expression changes in oxylipin biosynthetic
pathways. We determined functional-biochemical relevance of the proposed pathways
in rat hind paw and dorsal spinal cord by measuring basal and stimulated levels of
oxylipins throughout the time-course of carrageenan-induced inflammation. Finally,
when oxylipins were administered by intradermal injection we observed modulation of
nociceptive thermal hypersensitivity, providing a functional-behavioral link between
oxylipins, their molecular biosynthetic pathways, and involvement in pain and nociception.
Together, these findings advance our understanding of molecular lipidomic systems
linking oxylipins and their precursors to nociceptive and inflammatory signaling pathways
in rats.
Perspective
We applied a systems approach to characterize molecular pathways linking precursor
lipids and oxylipins to nociceptive signaling. This systematic, quantitative evaluation
of the molecular pathways linking oxylipins to nociception provides a framework for
future basic and clinical research investigating the role of oxylipins in pain.
Key words
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Article info
Publication history
Published online: October 05, 2020
Accepted:
September 24,
2020
Received in revised form:
August 31,
2020
Received:
June 30,
2020
Footnotes
A.F.D. and M.R.S. contributed equally to this work.
M.J.I. and C.E.R. contributed equally to this work.
This work was supported by the intramural research programs of the National Institute on Aging, National Institute on Alcohol Abuse and Alcoholism, National Center for Complementary and Integrative Health and the National Institutes of Health Clinical Center. Supplemental funding was provided by the NIH Benth-to-Bedside Program to M.J.I. from NCCIH, and the Office of Behavioral and Social Sciences. The NIA (NIH) has claimed intellectual property related to analogs of oxidized lipids (PCT/US2018/041086;), with C.E.R. and G.S.K. named as inventors.
The authors have no conflicts of interest to declare.
Identification
Copyright
© Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc.
