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 ω-6 PUFA-enriched diet 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. 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 novel etiology of peripheral neuropathy and risk factor for chronic pain, and implicate multiple therapeutic considerations for clinical pain management.

Spinal Reflex Control of Arterial Blood Pressure: The Role of TRP Channels and Their Endogenous Eicosanoid Modulators

“…Evidence to support this hypothesis was recently published by the laboratory of K.M. Hargeaves ( Boyd et al, 2021 ). Specifically, the authors observed that mice maintained on a diet with high ω-6 PUFA content displayed nociceptive hypersensitivities and C fiber hyper-responsivity when compared to animals maintained on a diet with low ω-6 PUFA content.…”

“…Evidence to support this hypothesis was recently published by the laboratory of K.M. Hargeaves (Boyd et al, 2021). Specifically, the authors observed that mice maintained…”

The Antinociceptive Potential of Camellia japonica Leaf Extract, (−)-Epicatechin, and Rutin against Chronic Constriction Injury-Induced Neuropathic Pain in Rats

“…Dynamic responses were assessed by stroking a cotton swab along the plantar surface of the rat’s hind paw, as described previously, with slight modifications [ 31 , 32 ]. The rats were acclimated for 30 min in the von Frey chambers.…”

Pathophysiological Consequences of At-Risk Alcohol Use; Implications for Comorbidity Risk in Persons Living With Human Immunodeficiency Virus

“…Evidence also suggests that diet and metabolic factors influence the development and chronicity of pain symptoms. Diets containing high amounts of omega-6 fatty acids (common in Western diets) exacerbate nociceptive sensitivity in preclinical animal models of neuropathic and inflammatory pain ( Boyd et al, 2021 ). Importantly, Western diets appear to prolong recovery from a pain-related injury in animals, although recovery was accelerated by switching animals to an anti-inflammatory diet ( Totsch et al, 2018 ).…”

“…Emerging evidence suggests that Western diets commonly consumed in the U.S. worsen both neurocognitive ( Martin and Davidson, 2014 ; Davidson et al, 2019 ) and pain symptomatology ( Boyd et al, 2021 ). Thus, the neurobiological interaction of excessive alcohol drinking, cognition, and pain in the context of WD consumption represents a critical area of research and public health interest.…”