Exploring the anti-hyperalgesic effects of ethyl gallate in fibromyalgia-like behaviors in mice

Fibromyalgia (FM) is a complex chronic pain disorder characterized by widespread musculoskeletal pain, affective disturbances, and cognitive impairments. Considering the limited efficacy of current treatments, novel agents with multimodal mechanisms are needed. This study investigated the drug-likeness, predicted molecular targets, and anti-hyperalgesic effects of ethyl gallate (EG), a naturally occurring phenolic ester, using in silico and in vivo approaches. The in vivo efficacy of EG was evaluated in two established murine models of FM: the reserpine-induced and acid-induced chronic widespread pain (CWP) models. Swiss mice were treated orally with EG (100 mg/kg) under preventive or therapeutic protocols. In silico analyses showed that EG (MW = 198.17 g/mol; ethyl 3,4,5-trihydroxybenzoate) possesses favorable physicochemical and pharmacokinetic properties, with good oral bioavailability, plasma stability, and safety. Target prediction identified several relevant proteins, including copper-containing enzymes, arylsulfate sulfotransferases, vitamin D₃ receptor, prostaglandin G/H synthase 1, glucocorticoid receptor, peroxisome proliferator-activated receptor delta (PPAR-δ), and toll-like receptors 1 and 2 (TLR1/TLR2), suggesting potential modulation of neuroinflammatory pathways. EG significantly reduced facial grimace pain scale, mechanical hyperalgesia, and thermal allodynia in both models compared with untreated controls. Moreover, EG produced an anti-anhedonic-like effect, evidenced by increased grooming behavior in the splash test following reserpine administration. In summary, EG demonstrates favorable in silico drug-like properties and robust oral anti-hyperalgesic effects in FM-like murine models. These findings highlight EG as a promising natural compound targeting neuro-immune and affective components of FM, warranting further translational and mechanistic studies.