In the present study, the activation of extracellular signal-regulated kinase (ERK) in the rostral ventromedial medulla (RVM) following the injection of complete Freund's adjuvant (CFA) into the rat hindpaw was examined in order to clarify the mechanisms underlying the dynamic changes in the descending pain modulatory system after peripheral inflammation. Phospho-extracellular signal-regulated kinase-immunoreactive (p-ERK-IR) neurons were observed in the nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis pars alpha (GiA). Inflammation induced the activation of ERK in the RVM, with a peak at 7 h after the injection of CFA into the hindpaw and a duration of 24 h. In the RVM, the number of p-ERK-IR neurons per section in rats killed at 7 h after CFA injection (14.2 +/- 1.7) was significantly higher than that in the control group (4.5 +/- 0.9) [P < 0.01]. At 7 h after CFA injection, about 60% of p-ERK-IR neurons in the RVM were serotonergic neurons. The percentage of RVM serotonergic neurons that are also p-ERK positive in the rats with inflammation (20.5% +/- 2.3%) was seven times higher than that in control rats (2.7% +/- 1.4%) [P < 0.01]. These findings suggest that inflammation-induced activation of ERK in the RVM may be involved in the plasticity in the descending pain modulatory system following inflammation.