This work was designed to investigate the antinociceptive effects of combinations of pioglitazone or metformin with fluoxetine in acute and persistent pain models in Swiss mice. Besides control groups, treatment groups (n=8) were given intraperitoneally (mg/kg) the following: fluoxetine (10, 20 and 40), pioglitazone (20), metformin (50), fluoxetine (20) + pioglitazone (20) and fluoxetine (20) + metformin (50). Sixty min post-injection, mice were subjected to three sets of experiments: 1) hot

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... te test (acute nociception), 2) formalin test (persistent pain) followed by measurement of paw edema, serum cytokines and immunoreactivity of glial fibrillary acidic protein (GFAP, a marker for astrocytic activation), and 3) rotarod test. In hot plate test, pretreatments with fluoxetine (20), fluoxetine (40), metformin, and the combinations significantly increased the latency time. Moreover, pretreatments with fluoxetine (40), pioglitazone, metformin and the combinations significantly decreased licking time in the second phase of formalin test, formalin-induced paw edema, and formalin-induced GFAP overexpression. All treatments significantly decreased serum levels of tumor necrosis factor-α, interleukin-6 and monocyte chemoattactant protein-1 while increased level of interleukin-10. In rotarod test, treatments did not affect motor function. In conclusion, combination of metformin with low-dose fluoxetine effectively inhibits nociceptive behavior in acute and persistent pain models in mice, suggesting its potential clinical benefit in treatment of pain comorbidities.