Objectives: The objectives of this review are to characterize the development and maintenance of chronic widespread muscle pain and to investigate the role of central mechanisms in the hyperalgesia in an animal model of chronic muscle pain.Findings: Two intramuscular injections of acidic saline, five days apart, result in bilateral mechanical hyperalgesia without peripheral tissue damage. The hyperalgesia only develops after the second intramuscular acid injection suggesting differences in neuronal responses between the first and second injection. In parallel to the bilateral hyperalgesia, there are bilateral increases in the spinal cord for the phosphorylation of the transcription factor, cyclic AMP responsive element binding protein [CREB], and ipsilateral dorsal horn neurons show an expansion of their receptive fields to include the contralateral hindlimb after the second injection. Supraspinally, blockade of neurotransmission in the rostral ventromedial medulla during the second intramuscular acid inj...