Eicosapentaenoic acid intake modulates programmed cell death protein 1 receptors to prevent chronic pain and comorbid depression in mice

Nutr Neurosci. 2026 Jun 3:1-17. doi: 10.1080/1028415X.2026.2678479. Online ahead of print.

ABSTRACT

BACKGROUND: Fibromyalgia is a frequently treatment-refractory chronic musculoskeletal pain disorder that often results in clinical depression; however, the role of neuroinflammatory signaling in comorbid depression remains unclear, including the contributions of anti-inflammatory omega-3 fatty acids like eicosapentaenoic acid (EPA).

METHODS: This study examined the efficacy of EPA ingestion for reducing chronic pain and depression comorbidity (CPDC) in a mouse model established using intermittent cold stress.

RESULTS: Our results showed that oral EPA could alleviate mechanical and thermal hyperalgesia in CPDC mice. The preventive effect of EPA on depressive symptoms in CPDC mice was further confirmed. Western blot and immunofluorescence staining revealed that EPA can inhibit the enhanced neuroinflammatory signaling concomitant with increased astrocyte and microglia activation and elevated levels of inflammatory signaling factors high-mobility group box 1 (HMGB1) and S100B in the CPDC mice. Alternatively, oral EPA can increase the attenuated expression of the pain-inhibiting programmed cell death protein 1 (PD-1) receptor. EPA intake can further alleviate inflammation-associated toll-like receptor 4 (TLR4) and downstream signaling molecules myeloid differentiation primary response 88 (MyD88), TNF receptor associated factor 6 (TRAF6), and activated (phosphorylated) nuclear factor kappa-light-chain-enhancer of activated B cells (pNFκB) in CPDC mouse brain. A similar response also observed in transient receptor potential vanilloid 1 gene knockout mice.

CONCLUSION: This demonstration that oral EPA can prevent CPDC by inhibiting neuroinflammatory pathways could facilitate improved treatment strategies for CPDC.

PMID:42233256 | DOI:10.1080/1028415X.2026.2678479