Pharmacological Interaction of Quercetin Derivatives of <i>Tilia americana</i> and Clinical Drugs in Experimental Fibromyalgia

Fibromyalgia (FM) is a pain syndrome characterized by chronic widespread pain and CNS comorbidities. Tilia americana var. mexicana is a medicinal species used to treat anxiety, insomnia, and acute or chronic pain. However, its spectrum of analgesic efficacy for dysfunctional pain is unknown. To investigate a possible therapeutic alternative for FM-type pain, an aqueous Tilia extract (TE) and its flavonoid fraction (FF) containing rutin and isoquercitrin were evaluated alone and/or combined with clinical drugs (tramadol—TRA and pramipexol—PRA) using the reserpine-induced FM model in rats. Chromatographic analysis allowed the characterization of flavonoids, while a histological analysis confirmed their presence in the brain. TE (10–100 mg/kg, i.p.) and FF (10–300 mg/kg, i.p.) produced significant and dose-dependent antihyperalgesic and antiallodynic effects equivalent to TRA (3–10 mg/kg, i.p.) or PRA (0.01–1 mg/kg, s.c.). Nevertheless, the combination of FF + TRA or FF + PRA resulted in an antagonistic interaction by possible competitive action on the serotonin transporter or µ-opioid and D2 receptors, respectively, according to the in silico analysis. Flavonoids were identified in cerebral regions because of their self-epifluorescence. In conclusion, Tilia possesses potential properties to relieve FM-type pain. However, the consumption of this plant or flavonoids such as quercetin derivatives in combination with analgesic drugs might reduce their individual benefits