Opioid agents have been shown to protect against tissue damage caused by hypoxia/reperfusion, an event which has a significant reactive-oxygen-species (ROS) involvement. We have investigated the potential anti-inflammatory activity of three opioid agonists, DAMGO, DPDPE and U50488 in rat skin inflammation induced by the ROS hydrogen peroxide. The model involves the intradermal injection of the enzyme glucose oxidase which converts glucose to D-gluconic acid and H2O2 which is locally released. Following injection, a well-delineated inflammatory response develops rapidly, is maximal at 5 h and still measurable after 48 h. Co-administration of the δ or κ opioid agonists DPDPE or U50488 (7.5-60 μg per site) significantly reduced the inflammation, in a dose-dependent manner, for periods of up to 3 h for DPDPE, and up to 5 h with U50488. The μ-opioid agonist DAMGO (7.5-60 μg per site) was ineffective. Co-administration of the opioid antagonist naltrexone (120 μg) partially reversed the anti-inflammatory effects of DPDPE and U50488. We conclude that the δ and κ opioid receptor agonists DPDPE and U50488 are able to inhibit ROS-induced skin inflammation and that this may have clinical implications.