Sesquiterpene lactones possess a variety of biological activities, including anti-inflammatory activity. Two plants native to the southeastern United States, Magnolia grandiflora (L.) and Smallanthus uvedalius (L.) [syn Polymnia uvedalius (L.)], are novel sources of the sesquiterpene lactones parthenolide and enhydrin, respectively. In this study, the anti-inflammatory and anti-hyperalgesic effects of these isolated lactones from these two plant sources were evaluated in the rat carrageenan inflammation model. Rats received ip injections of either vehicle (propylene glycol), indomethacin (5 mg/kg), 11,13-dihydroparthenolide (20 mg/kg), parthenolide (5 or 20 mg/kg) or enhydrin (5 or 20 mg/kg). A 100-microl injection of 2.0% carrageenan was made into the plantar surface of the right hindpaw. Paw withdrawal latencies and paw volumes in both inflamed and non-inflamed paws were recorded at four test intervals: pre-inflammation baseline (0 time point), and 1, 2 and 4 h post-carrageenan injection. Vehicle-treated animals exhibited a significant time-dependent hyperalgesic and edema response that was greatest at the 4-h test interval. Indomethacin significantly blocked the hyperalgesic response and modestly attenuated the edema response. Parthenolide (20 mg/kg) and enhydrin (20 mg/kg) significantly blocked the hyperalgesic response and significantly attenuated the edema response; 11,13-dihydroparthenolide did not affect either inflammation or hyperalgesia. These findings suggest that parthenolide and enhydrin from these plant sources may be useful in the treatment of inflammatory pain.