Abstract
Intrathecal pretreatment with N-methyl-d-aspartate (NMDA) receptor antagonists blocks development of spinal sensitization in a number of pain models. In contrast, secondary mechanical allodynia evoked by thermal injury (52.5°C for 45 s) applied to the hind paw of the rat is not blocked by intrathecal pretreatment with NMDA receptor antagonists. It is, however, blocked by antagonists to the non-NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate (AMPA/KA) and calcium-permeable AMPA/KA receptors. These findings suggest a role for these receptors in the development of spinal sensitization. The present study used the same thermal injury model to assess the effects of the AMPA/KA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and specific calcium-permeable AMPA/KA receptor antagonists philanthotoxin (PHTx) and joro spider toxin (JST) when given as postinjury treatments. Intrathecal saline injection at 5 and 30 min postinjury had no effect on thermal injury-evoked allodynia as measured by calibrated von Frey filaments. In contrast, 36 nmol of CNQX given at either time point reversed allodynia. Intrathecal 13 nmol of PHTx or 9 nmol of JST (higher doses than that required for pretreatment) reversed allodynia at the 5-min time point, but neither drug was antiallodynic at the 30-min time point. Thus, secondary mechanical allodynia in this model is not maintained by calcium-permeable AMPA/KA receptors, but instead requires activation of calcium-impermeable AMPA/KA receptors. This finding supports a role for AMPA/KA receptor function in responses occurring during spinal sensitization.
Footnotes
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This work was supported by National Science Foundation Grant 41580 (to L.S.S.).
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DOI: 10.1124/jpet.103.064741.
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ABBREVIATIONS: NMDA, N-methyl-d-aspartate; AMPA/KA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate; GLU, glutamate; CNQX, 6-cyano-7-nitroquinoxaline; Ca2+-perm-AMPA/KA, calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate; JST, joro spider toxin; PHTx, philanthotoxin; AUC, area under the curve; ANOVA, analysis of variance; CaM-kinase IIα, calcium/calmodulin-dependent kinase IIα.
- Received January 12, 2004.
- Accepted February 23, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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