@article{cb78913fa8c24baf89b863c529b4565d,
title = "Elevated dietary ω-6 polyunsaturated fatty acids induce reversible peripheral nerve dysfunction that exacerbates comorbid pain conditions",
abstract = "Chronic pain is the leading cause of disability worldwide1 and is commonly associated with comorbid disorders2. However, the role of diet in chronic pain is poorly understood. Of particular interest is the Western-style diet, enriched with ω-6 polyunsaturated fatty acids (PUFAs) that accumulate in membrane phospholipids and oxidise into pronociceptive oxylipins3,4. Here we report that mice administered an ω-6 PUFA-enriched diet develop persistent nociceptive hypersensitivities, spontaneously active and hyper-responsive glabrous afferent fibres and histologic markers of peripheral nerve damage reminiscent of a peripheral neuropathy. Linoleic and arachidonic acids accumulate in lumbar dorsal root ganglia, with increased liberation via elevated phospholipase (PLA)2 activity. Pharmacological and molecular inhibition of PLA2G7 or diet reversal with high levels of ω-3 PUFAs attenuate nociceptive behaviours, neurophysiologic abnormalities and afferent histopathology induced by high ω-6 intake. Additionally, ω-6 PUFA accumulation exacerbates allodynia observed in preclinical inflammatory and neuropathic pain models and is strongly correlated with multiple pain indices of clinical diabetic neuropathy. Collectively, these data reveal dietary enrichment with ω-6 PUFAs as a new aetiology of peripheral neuropathy and risk factor for chronic pain and implicate multiple therapeutic considerations for clinical pain management.",
author = "Boyd, {Jacob T.} and LoCoco, {Peter M.} and Furr, {Ashley R.} and Bendele, {Michelle R.} and Meilinn Tram and Qun Li and Chang, {Fang Mei} and Colley, {Madeline E.} and Samenuk, {Grace M.} and Arris, {Dominic A.} and Locke, {Erin E.} and Bach, {Stephan B.H.} and Alejandro Tobon and Ruparel, {Shivani B.} and Hargreaves, {Kenneth M.}",
note = "Funding Information: The project described was supported in part by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through grant UL1TR002645 (K.M.H.). Additional support from the NIH includes grants R01NS110948 (K.M.H.), T32DE14318 (P.M.L., A.R.F., K.M.H.), T32GM113896 (J.T.B.), F30AT009949 (J.T.B.), F32DK118841 (P.M.L.), F30DE028486 (A.R.F.) and a grant from the Ella and Williams Owen{\textquoteright}s Foundation (K.M.H.). Clinical data were managed using REDCap software supported by UL1RR024982. Certain mass spectrometric analyses were carried out on equipment supported by the US Department of Agriculture, Agricultural Research Service, under agreement no. 58-3094-8-012. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the US Department of Agriculture. We thank X. Han and his laboratory for expertise and guidance on shotgun lipidomics. We thank M. Patil and P. Wu for technical assistance as well as A. Diogenes, N. Ruparel, A. Khan and A. Akopian for fruitful discussions. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2021",
month = jun,
doi = "10.1038/s42255-021-00410-x",
language = "English (US)",
volume = "3",
pages = "762--773",
journal = "Nature Metabolism",
issn = "2522-5812",
publisher = "Springer Berlin",
number = "6",
}