Background:Codiaeumvariegatum, sometimes called garden croton, is a tropical plant in the Euphorbiaceae family. Historically used to cure various conditions, including intestinal infections, fever, ulcers, wounds, and gonorrhea. This work aimed to investigate the antinociceptive effects of ethanolic extract of Codiaeumvariegatum leaves (EECV) in animal models. Methods: Five different pain models—the hot plate, tail immersion, acetic acid-induced writhing, formalin, and glutamate-induced nociception tests—were utilized to assess the antinociceptive activity in mice. The traditional drugs such as diclofenac sodium (10 mg/kg, i.p.) and morphine sulphate (5 mg/kg). EECV was administered orally at varying doses of 100, 200, and 300 mg/kg (0.1 mL/mouse), while the control group was given deionized water. Results: The current study found that all mouse models of heat- and chemical-induced pain had robust EECV reflections of their antinociceptive properties (*p < 0.05). In the hot plate and tail immersion tests, 200 and 300 mg/kg showed a significant (*p < 0.05) capacity to delay the reaction of latency to pain in contrast to thermally induced nociception. The levels of inhibition in the acetic acid-induced writhing test were 20.07%, 44.86%, and 59.87% for 100, 200, and 300 mg/kg doses, respectively. The extract prevented 18.89%, 44.88%, and 59.84% of licking during the early stages of formalin-induced nociception at varying doses of 100, 200, and 300 mg/kg. Compared to the control group, the extract exhibited higher licking rates throughout the late phase (28.78%, 48.48%, and 54.54%). The plant extract considerably (*p < 0.05) reduced the glutamate-induced nociception test. Compared to the control, it showed 13.07%, 52.30%, and 76.92% for 100, 200, and 300 mg/kg doses, respectively. Conclusions: The current finding offers a fresh perspective on the ethanolic extract of Codiaeumvariegatum leaves’ antinociceptive properties in mice. This plant’s phytochemical analysis revealed the presence of triterpenoids, sterols, alkaloids, flavonoids, and general glycosides, all of which may have antinociceptive properties. More research on the mechanism of action and associated pharmacological studies, such as in vivo analysis, medication formulation, and clinical trials, is strongly advised.
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