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 worldwide 1 and commonly associated with comorbid disorders 2 . 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 oxidize into pronociceptive oxylipins 3,4 . Here we report that mice administered a diet enriched with ω-6 PUFAs develop persistent nociceptive hypersensitivities, spontaneously-active and hyper-responsive glabrous afferent fibers, 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 PLA2 activity. Pharmacological and molecular inhibition of PLA2g7 or diet reversal with high ω-3 PUFAs attenuate nociceptive behaviors, neurophysiologic abnormalities, and afferent histopathology induced by high ω-6 intake. In addition, ω-6 accumulation exacerbates the intensity or duration of allodynia observed in preclinical inflammatory and neuropathic pain models, as well as in clinical diabetic neuropathy. Collectively, these data reveal diet as a novel etiology of peripheral neuropathy and risk factor for chronic pain, and implicate multiple therapeutic considerations for clinical pain management.

Chronic Overlapping Pain Conditions and Nociplastic Pain

“…Changes in amino acid levels are associated with fibromyalgia, migraine, osteoarthritis and complex regional pain syndrome (51). High acylcarnitine levels can indicate disorders in fatty acid metabolism, and diets high in certain fatty acids have been associated with increased allodynia in rodent models, and associated with human chronic pain conditions (52). Lipids generally are also involved in acute and chronic inflammation (53) and changes to acylcarnitine metabolism are observed in dementia, certain cancers, heart failure and coronary artery disease (54).…”