4-Hydroxycoumarin Exhibits Antinociceptive and Anti-Inflammatory Effects Through Cytokine Modulation: An Integrated In Silico and In Vivo Study

Chronic pain significantly impacts quality of life and is often accompanied by inflammation, a natural bodily response that can become harmful when excessive. The orofacial region is commonly affected, making effective treatment crucial. However, current drugs often cause undesirable side effects, highlighting the need for new pharmacological alternatives. 4-hydroxycoumarin (4-HC), a natural compound, has shown promising antinociceptive and anti-inflammatory effects, but studies confirming its specific properties are limited. In silico analyses suggest that 4-HC exhibits favorable pharmacokinetic characteristics, not interacting with P-glycoprotein and successfully crossing the blood-brain barrier. Molecular docking studies indicate that its effects may be mediated through NMDAR or by inhibiting iNOS. Our study assessed the antinociceptive and anti-inflammatory effects of 4-HC in animal models at doses of 25, 50, and 75 mg/kg. 4-HC significantly reduced abdominal contortions induced by acetic acid and decreased nociceptive rubbing in orofacial pain models induced by formalin, glutamate, and capsaicin. Interactions with opioid receptors were not observed, suggesting that 4-HC’s antinociceptive effect does not involve this pathway. Additionally, 4-HC reduced paw edema induced by carrageenan and significantly decreased leukocyte migration and TNF-α levels. These findings highlight the therapeutic potential of 4-HC and warrant further investigation into its mechanisms.