Characterization of a model of non-inflammatory muscle-induced pain: Ionotropic glutamate receptor involvement

The acid model is induced by two injections of acidic saline, 5 days apart, into the gastrocnemius muscle of rat. Mechanical hyperalgesia of the paw develops within hours after the second injection, but not after the first injection. Further, the hyperalgesia spreads to the contralateral hindlimb and is long-lasting. Once developed the secondary hyperalgesia is not dependent upon input from the site of injection. This suggests that central neuronal mechanisms maintain the hyperalgesia and that there is a differential response to the second injection as compared to the first injection. The studies described in this dissertation investigated the contribution of spinal ionotropic glutamate receptors to secondary mechanical hyperalgesia in this model of chronic muscle pain.; Behavioral pharmacology experiments were used to determine if blockade of spinal NMDA or AMPA/kainate glutamate receptors prior to i.m. acid injection or one week after the second acid injection prevented or reversed secondary hyperalgesia. Spinal microdialysis was performed to determine if i.m. acid injection increased extracellular glutamate or aspartate concentrations in the dorsal horn and if basal excitatory amino acid (EAA) concentrations were increased during the maintenance phase of hyperalgesia. Experiments utilizing Western blotting were performed to determine if AMPA receptor number or phosphorylation was increased in the dorsal horn of the spinal cord during the maintenance phase of hyperalgesia.; Findings from these experiments suggest that development of secondary hyperalgesia in this model is dependent on spinal NMDA receptor activation and maintenance of hyperalgesia is dependent on spinal AMPA/kainate and NMDA glutamate receptor activation. Further, the second i.m. acid injection evokes an increased release of EAAs in the dorsal horn, and basal extracellular glutamate concentrations are increased one week after the second i.m. injection of acid. However, spinal AMPA receptor number and C-terminus phosphorylation does not change during the maintenance phase of hyperalgesia.; From these findings, I conclude that hyperalgesia develops as a result of increased spinal EAA release after the second acid injection, which activates NMDA glutamate receptors. The hyperalgesia is then maintained in part by increased glutamate activating NMDA and non-NMDA glutamate receptors within the spinal dorsal horn.