Enhancing analgesic and anti-inflammatory synergetic effect with Naringenin: In-silico and in vivo investigation

Chronic inflammation and pain are major clinical challenges, often requiring pharmacological intervention. While NSAIDs like Aceclofenac and opioid analgesics such as Pentazocine are effective, their long-term use is associated with adverse effects. Naringenin, a natural bioactive compound, has demonstrated promising anti-inflammatory and analgesic properties, suggesting potential for combination therapy to enhance efficacy and reduce side effects. This study investigates the synergistic effects of Naringenin with Aceclofenac and Pentazocine through molecular docking and in vivo animal models. Molecular docking revealed strong binding interactions of Naringenin with COX-2 (-9.1 kcal/mol), μ-opioid receptors (-7.8 kcal/mol), and TNF-α (-7.6 kcal/mol), indicating potential analgesic and anti-inflammatory activity. Acetic acid-induced writhing test (peripheral analgesic activity) effects showed highly significant inhibition (***p<0.001) at both high (21.83 ± 1.276, 100 mg/kg, p.o.) and low (23.33 ± 0.881, 50 mg/kg, p.o.) doses of Aceclofenac combined with Naringenin (200 mg/kg, p.o.). The hotplate test (central analgesic activity) revealed a highly significant response (***p<0.001) after 30 min at high (12.33±0.494, 10 mg/kg, iv.) and low (11.00±0.365, 5 mg/kg, iv.) doses of Pentazocine with Naringenin. Carrageenan-induced paw edema (anti-inflammatory effect) showed significant inhibition (***p<0.001) at similar dose combinations after 1 hr (high dose, 0.422±0.020 and low dose, 0.444±0.015) Additionally, inflammatory biomarkers CRP and TNF-α exhibited highly significant reductions (***p<0.001), while IL-6 (showed significant reduction (**p<0.01). These findings suggest that Naringenin enhances the therapeutic efficacy of Aceclofenac and Pentazocine, offering a potential combinatorial strategy for safer and more effective pain and inflammation management.