Statins are widely used in cardiovascular disease as cholesterol lowering drugs. However, they also have other actions (pleiotropic effects) including antiproliferative, antithrombotic, neuroprotective, immunomodulatory, anti-inflammatory and antinociceptive activity. The aim of this study was to determine the antinociception properties of rosuvastatin in two murine models of pain and the involvement of opioid antagonists (naltrexone, naltrindole, norbinaltorphimine), risperidone, and L-NAME (L-NG-nitro arginine methyl ester) in this effect. Rosuvastatin was chosen among available statins because it is commonly prescribed and has high potency, efficacy, and an acceptable safety profile. Rosuvastatin antinociception was evaluated in the acetic acid writhing test and the formalin hind paw test by dose-response curves, before and after the i.p. administration of opioid antagonists, risperidone, and L-NAME. This work demonstrates that the assayed drugs modulate the antinociceptive effect of rosuvastatin in both experimental murine pain tests. The antinociception effect described for rosuvastatin may be due to a particular modulation induced by the opioid antagonists, risperidone and L-NAME. Given the broad effects of rosuvastatin, the results of this study may have novel clinical implications in the therapy of pain.