Thalamic NMDA receptors modulate inflammation-produced hyperalgesia in the rat.

摘要

The effects of inhibition of thalamic NMDA receptor function and synthesis on thermal and mechanical hyperalgesia induced by hindlimb intraplantar injection of carrageenan in the rat were studied in the 'acute' phase (within 3-5 h) and the 'subacute' phase (24 h) after carrageenan administration. Blockade of NMDA receptors was produced by intrathalamic injection of D,2-amino-5-phosphonovaleric acid (D-APV) and NMDA receptor synthesis was decreased (or not) by pretreatment of rats with intrathalamic (hindlimb representation area) injections of antisense, sense or missense oligodeoxynucleotides (ODNs) directed against the NR1 subunit of the NMDA receptor complex. Treatment with D-APV, but not saline, in the contralateral (but not ipsilateral) thalamus significantly reduced both the acute thermal and mechanical hyperalgesia in the injected paw; these same rats demonstrated significantly less thermal and mechanical hyperalgesia in the sub-acute phase than rats that had received saline or D-APV in the ipsilateral thalamus. None of the treatments had any effect on withdrawal responses of the uninjected hindpaw. Rats pretreated with NR1 sense or missense ODNs developed both thermal and mechanical hyperalgesia that was equivalent in magnitude and duration to rats that received intrathalamic saline injections. In contrast, rats pretreated with NR1 antisense ODN did not develop either acute or subacute thermal hyperalgesia; they developed less mechanical hyperalgesia than saline, sense or missense ODN-treated rats. Antisense ODN-treated rats also displayed a decrease in the number of thalamic NMDA receptors as determined by receptor binding assay. These results suggest an involvement of thalamic NMDA receptors in the development and maintenance of hyperalgesia associated with neurogenic inflammation in a model of tonic pain.