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Atorvastatin is an inhibitor of the enzyme 3-hydroxyl-3-methylglutaryl coenzyme A reductase used to prevent coronary heart disease. We have studied the analgesic effect of atorvastatin in inflammatory models in which a sequential release of mediators (bradykinin, (BK), tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and the chemokine, KC/CXCL) links the stimulus with release of directly acting hypernociceptive mediators such as prostaglandin E2 (PGE2).The effects of orally administered atorvastatin on inflammatory mechanical hypernociception in mouse paws were evaluated with an electronic pressure-meter. Cytokines and PGE2 were measured by ELISA and RIA.Treatment with atorvastatin for 3 days dose-dependently reduced hypernociception induced by lipopolysaccharide (LPS) or that following antigen challenge in sensitized animals. Atorvastatin pre-treatment reduced hypernociception induced by bradykinin and cytokines (TNF-α, IL-1β and KC), and the release of IL-1β and PGE2 in paw skin, induced by lipopolysaccharide. The antinociceptive effect of atorvastatin on LPS-induced hypernociception was prevented by mevalonate co-treatment without affecting serum cholesterol levels. Hypernociception induced by PGE2 was inhibited by atorvastatin, suggesting intracellular antinociceptive mechanisms for atorvastatin. The antinociceptive effect of atorvastatin upon LPS- or PGE2-induced hypernociception was prevented by non-selective inhibitors of nitric oxide synthase (NOS) but not by selective inhibition of inducible NOS or in mice lacking this enzyme.Antinociceptive effects of atorvastatin depend on inhibition of cytokines and prostanoid production and on stimulation of NO production by constitutive NOS. Our study suggests that statins may constitute a novel class of analgesic drugs.