Extracellular signal-regulated kinase (ERK) is a key molecule in numerous cellular and physiological processes in the CNS. Exposure to stressors causes substantial effects on the perception and response to pain. The rostral ventromedial medulla (RVM) and the locus coeruleus (LC) play crucial roles in descending pain modulation system. In the present study, the activation of ERK in the RVM and the LC in rats following acute and chronic restraint stress was examined in order to characterize the mechanisms underlying stress induced analgesic and hyperalgesic responses. Rats were stressed by restraint 6 h daily for 3 weeks. The acute and chronic restraint stresses produced analgesic and hyperalgesic reactions, respectively, to thermal stimuli applied to the tail. The phospho-ERK-immunoreactive (p-ERK-IR) neurons were observed in the nucleus raphe magnus (NRM), nucleus reticularis gigantocellularis pars alpha (GiA) and LC. In the RVM, the number of p-ERK-IR neurons per section in the 3-week restraint rats (14.3+/-1.2) was significantly higher than that in the control rats (8.9+/-0.7) [P<0.01]. About 75% of p-ERK-IR neurons in the RVM in the 3-week restraint rats were serotonergic neurons. Protein levels of tryptophan hydroxylase were significantly increased in the RVM region in the 3-week restraint rats. On the other hand, the chronic restraint stress significantly decreased p-ERK-IR in the LC [P<0.05]. These findings suggest that chronic restraint stress-induced activation of ERK in the RVM and the suppression in the LC may be involved in the modulation of the pain threshold by chronic stress. (C) 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.