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Desalegn Getnet Demsie,1,2 Ebrahim M Yimer,1 Abera Hadgu Berhe,1 Birhanetensay Masresha Altaye,3 Derbew Fikadu Berhe11Department of Pharmacology and Toxicology, College of Health Sciences, Mekelle University, Mekelle, Ethiopia; 2Department of Pharmacy, College of Medicine and Health Sciences, Adigrat University, Adigrat, Ethiopia; 3Department of Pharmacy, College of Medicine, Debre Berhan University, Debre Berhan, EthiopiaBackground: Societies in developing countries use traditional medicine as alternatives for management of pain and inflammation. The plant Cucumis ficifolius has been used in Ethiopia to treat many ailments including inflammation and pain. The objective of this study was to evaluate the antinociceptive and anti-inflammatory activities of the crude root extract and solvent fractions of C. ficifolius.Methods: The analgesic activity of crude extract and solvent fractions of C. ficifolius was evaluated with acetic acid-induced writhing, hot plate, and formalin-induced paw licking tests. The anti-inflammatory effect of crude methanolic root extract and solvent fractions of C. ficifolius was evaluated using carrageenan-induced paw edema. The crude extract was given at 200, 400 and 800 mg/kg. Butanol and aqueous fractions were given at 100 and 200 mg/kg doses. The negative control groups were treated with distilled water (10 mL/kg). Standard drugs used wereacetylsalicylic acid(ASA) in acetic acid, formalin tests and carrageenan-induced paw edema and morphine (20 mg/kg) in hot plate test.Results: The crude extract, at its maximum dose, produced comparable analgesic activity (72.5%) to ASA in acetic acid writhing test. In the hot plate test, both the crude extract and solvent fractions exhibited a significant prolongation of nociception reaction time. Formalin test result indicated a significant reduction of mean lick time with maximal protection of 64% (early phase) and 83% (late phase). Aqueous and butanol fractions showed good analgesic activity in the three models. Inflammation was decreased by 69% with butanol (200 mg/kg); 71% (800 mg/kg) of crude extract and by 41% and 56% with the use of aqueous fraction at 100 and 200 mg/kg, respectively (p