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Introduction The analgesic effect of copper(II) coordination complexes with non-steroidal antiinflammatory drugs (NSAIDs) is an issue of debate. Some authors sustain that the analgesic action becomes enhanced when the NSAID forms a coordination compound with copper(II) (1), meanwhile others have found that the complexation does not produce changes on the analgesic effect of the parent drug (2). In this work, we investigate the analgesic effect of two new copper(II) coordination complexes with the non steroidal anti-inflammatory drug Fenoprofen, Cu2(Fen)4(dmf)2 (Fen: fenoprofenate anion; dmf: dimethylformamide) and Cu2(Fen)4(caf)2 (caf: cafeine) using acetic acid-induced writhes and formalin test. These two different analgesic testing models were employed with the aim of identifying peripheral and central effects of the test substances. Acetic acid produces a painful reaction and acute inflammation in the peritoneal area and induces abdominal writhing which is a visceral pain model (3,4). The formalin test is considered a model for pain (5) and it is an effective way to measure the peripheral and central pain.2(Fen)4(dmf)2 (Fen: fenoprofenate anion; dmf: dimethylformamide) and Cu2(Fen)4(caf)2 (caf: cafeine) using acetic acid-induced writhes and formalin test. These two different analgesic testing models were employed with the aim of identifying peripheral and central effects of the test substances. Acetic acid produces a painful reaction and acute inflammation in the peritoneal area and induces abdominal writhing which is a visceral pain model (3,4). The formalin test is considered a model for pain (5) and it is an effective way to measure the peripheral and central pain.2(Fen)4(caf)2 (caf: cafeine) using acetic acid-induced writhes and formalin test. These two different analgesic testing models were employed with the aim of identifying peripheral and central effects of the test substances. Acetic acid produces a painful reaction and acute inflammation in the peritoneal area and induces abdominal writhing which is a visceral pain model (3,4). The formalin test is considered a model for pain (5) and it is an effective way to measure the peripheral and central pain. Materials and methods The synthesis of Cu2(Fen)4(dmf)2 has been previously described (6). From this one dissolved in acetone, Cu2(Fen)4(caf)2 was prepared by the addition of an ethanolic solution of caffeine. After the reaction, crystals were obtained by the diffusion of acetonitrile. For the writhing test, four groups of mice were orally treated with Cu2(Fen)4(dmf)2 (26 mg/kg ), Cu2(Fen)4(caf)2 (31 mg/kg), Fenoprofen calcium salt as uncomplexed parent drug (21mg/kg), and the control one which received only vehicle (1% CMC, 0.1% Tween80). Then, 60 minutes later nociception was induced by an intraperitoneal injection of 0.5% acetic acid solution (10mL/kg). After injection, each animal was isolated in an individual box to be observed during 20 minutes. The number of writhing and stretching was recorded.2(Fen)4(dmf)2 has been previously described (6). From this one dissolved in acetone, Cu2(Fen)4(caf)2 was prepared by the addition of an ethanolic solution of caffeine. After the reaction, crystals were obtained by the diffusion of acetonitrile. For the writhing test, four groups of mice were orally treated with Cu2(Fen)4(dmf)2 (26 mg/kg ), Cu2(Fen)4(caf)2 (31 mg/kg), Fenoprofen calcium salt as uncomplexed parent drug (21mg/kg), and the control one which received only vehicle (1% CMC, 0.1% Tween80). Then, 60 minutes later nociception was induced by an intraperitoneal injection of 0.5% acetic acid solution (10mL/kg). After injection, each animal was isolated in an individual box to be observed during 20 minutes. The number of writhing and stretching was recorded.2(Fen)4(caf)2 was prepared by the addition of an ethanolic solution of caffeine. After the reaction, crystals were obtained by the diffusion of acetonitrile. For the writhing test, four groups of mice were orally treated with Cu2(Fen)4(dmf)2 (26 mg/kg ), Cu2(Fen)4(caf)2 (31 mg/kg), Fenoprofen calcium salt as uncomplexed parent drug (21mg/kg), and the control one which received only vehicle (1% CMC, 0.1% Tween80). Then, 60 minutes later nociception was induced by an intraperitoneal injection of 0.5% acetic acid solution (10mL/kg). After injection, each animal was isolated in an individual box to be observed during 20 minutes. The number of writhing and stretching was recorded.2(Fen)4(dmf)2 (26 mg/kg ), Cu2(Fen)4(caf)2 (31 mg/kg), Fenoprofen calcium salt as uncomplexed parent drug (21mg/kg), and the control one which received only vehicle (1% CMC, 0.1% Tween80). Then, 60 minutes later nociception was induced by an intraperitoneal injection of 0.5% acetic acid solution (10mL/kg). After injection, each animal was isolated in an individual box to be observed during 20 minutes. The number of writhing and stretching was recorded.2(Fen)4(caf)2 (31 mg/kg), Fenoprofen calcium salt as uncomplexed parent drug (21mg/kg), and the control one which received only vehicle (1% CMC, 0.1% Tween80). Then, 60 minutes later nociception was induced by an intraperitoneal injection of 0.5% acetic acid solution (10mL/kg). After injection, each animal was isolated in an individual box to be observed during 20 minutes. The number of writhing and stretching was recorded. For the formalin test, 20 ¦Ìl of 2,5 % formalin was injected into the dorsal surface of the left paw of mice, one hour after oral administration of complexes, Fenoprofen calcium salt or vehicle. The time that animals spent on licking the injected paw was recorded. Two distinct periods of intensive licking activity were identified and scored separately. The inicial nociceptive scores normally peaked 5 minutes after formalin injection (early phase) and 15-30 minutes after injection (late phase), representing both the neurogenic and inflammatory pain responses, respectively. Results Acetic acid-induced writhing Treatment with Cu2(Fen)4(dmf)2, Cu2(Fen)4(caf)2 and Fenoprofen salt groups significantly decreased the acetic acid-induced writhing response compared with the control: 89,7 % (p<0.001), 89,8 % (p<0.001) and 45,2 % (p<0.05), respectively. When Fenoprofen calcium salt was compared to the complexes, both Cu2(Fen)4(dmf)2 and Cu2(Fen)4(caf)2 decreased more effectively the visceral pain (p< 0.001).2(Fen)4(dmf)2, Cu2(Fen)4(caf)2 and Fenoprofen salt groups significantly decreased the acetic acid-induced writhing response compared with the control: 89,7 % (p<0.001), 89,8 % (p<0.001) and 45,2 % (p<0.05), respectively. When Fenoprofen calcium salt was compared to the complexes, both Cu2(Fen)4(dmf)2 and Cu2(Fen)4(caf)2 decreased more effectively the visceral pain (p< 0.001).p<0.001), 89,8 % (p<0.001) and 45,2 % (p<0.05), respectively. When Fenoprofen calcium salt was compared to the complexes, both Cu2(Fen)4(dmf)2 and Cu2(Fen)4(caf)2 decreased more effectively the visceral pain (p< 0.001).2(Fen)4(dmf)2 and Cu2(Fen)4(caf)2 decreased more effectively the visceral pain (p< 0.001).p< 0.001). Formalin test The time spent on licking the injured paw was significantly attenuated in the early phase by complexes and Fenoprofen salt, but Cu2(Fen)4(dmf)2 and Cu2(Fen)4(caf)2 showed marked inhibition (p < 0.001) of licking responses in the late phase when compared to the control and to the uncomplexed parent drug.2(Fen)4(dmf)2 and Cu2(Fen)4(caf)2 showed marked inhibition (p < 0.001) of licking responses in the late phase when compared to the control and to the uncomplexed parent drug.p < 0.001) of licking responses in the late phase when compared to the control and to the uncomplexed parent drug. Conclusion The results found in this work indicate that, although Cu2(Fen)4(dmf)2 and Cu2(Fen)4(caf)2 produce similar effect than Fenoprofen calcium salt in central pain, both complexes present a more potent analgesic effect for peripheral pain.2(Fen)4(dmf)2 and Cu2(Fen)4(caf)2 produce similar effect than Fenoprofen calcium salt in central pain, both complexes present a more potent analgesic effect for peripheral pain.2(Fen)4(caf)2 produce similar effect than Fenoprofen calcium salt in central pain, both complexes present a more potent analgesic effect for peripheral pain. References (1) Okuyama S, Hashimoto S, Aihara H, Willingham W, Sorenson JRJ. Copper complexes of non-steroidal antiinflammatory agents: Analgesic activity and possible opioid receptor activation. Inflammation Research 1987 Jun; 21:130-144. (2) Oga S, Taniguchi SF, Najjar R, Souza AR. Synthesis, characterization, and biological screening of a copper flurbiprofen complex with anti-inflammatory effects. 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