ABSTRACT: We previously showed that the progression of burn-induced injury was inhibited by exposing the peripheral area of injured skin to sublethal hyperthermia following the burn. We called this phenomenon post-heat shock tolerance. Here we suggest a mechanism for this phenomenon. Exposure of the peripheral primary hyperalgesic/allodynic area of burned skin to local hyperthermia (45 degrees C, 30 seconds), which is a non-painful stimulus for normal skin, results in a painful sensation transmitted by nociceptors. This hyperthermia is too mild to induce any tissue injury, but it does result in pain due to burn-induced hyperalgesia/allodynia. This mild painful stimulus can result in the induction of descending anti-nociceptive mechanisms, especially in the adjacent burned area. Some of these inhibitory mechanisms, such as alterations of sympathetic outflow and the production of endogenous opioids, can modify peripheral tissue inflammation. This decrease in burn-induced inflammation can diminish the progression of burn injury.