Centering on Central Mechanisms in the Development and Maintenance of Chronic Widespread Muscle Pain

Abstract

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 injection prevents the development hyperalgesia and reverses the previously developed hyperalgesia. There is also increased release of glutamate in response to the second intramuscular injection both spinally and supraspinally, and blockade of N-methyl-D-aspartic acid receptors spinally or supraspinally delays the onset of hyperalgesia.

Conclusions: Two intramuscular injections of acidic saline results in widespread mechanical hyperalgesia of the paw, muscle, and viscera, and mimics chronic widespread pain in humans. There is increased excitability in the spinal cord and the rostral ventromedial medulla that results from increases in glutamate, activation of NMDA receptors and activation of the cyclic AMP pathway that are critical for the development and maintenance of chronic widespread muscle pain.

KEYWORDS:

• Hyperalgesia
• fibromyalgia syndrome
• glutamate
• cAMP
• review