Pain Models Display Differential Sensitivity to Ca2+-Permeable Non-NMDA Glutamate Receptor Antagonists

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Abstract

Background

Ca2+-permeable non–N-methyl-d-aspartate receptors are found in the spinal dorsal horn and represent a presumptive target for glutamatergic transmission in nociceptive processing. This study characterized the analgesic profile associated with the blockade of these spinal receptors by intrathecally delivered agents known to act at these receptors, the spider venom Joro toxin (JST) and philanthotoxin.

Methods

Philanthotoxin (0.5, 2.5, or 5 μg) or JST (5 μg) was given spinally before thermal injury to the paw. JST (5 μg) was also given 10 min before subcutaneous formalin injection, after intraplantar administration of carrageenan, and to rats that were allodynic due to tight ligation of spinal nerves. Lower doses of JST (0.25 and 1.0 μg) were given before formalin injection and testing of thermal latencies. Thermal latencies were measured using a Hargreaves box, mechanical thresholds using von Frey hairs, and formalin response by means of counting flinches.

Results

Both agents blocked thermal injury–induced mechanical allodynia. JST (5 μg) given 1 h after carrageenan blocked induction of thermal hyperalgesia and mechanical allodynia. JST (5 μg) had no effect in the formalin test, on allodynia after spinal nerve ligation, or when given 3 h after carrageenan. The lowest dose (0.25 μg JST) at pretreatment intervals of 60–120 min resulted in modest hypoalgesia during phase 1 formalin and thermal testing.

Conclusions

The behavioral effect of intrathecal Ca2+-permeable non–N-methyl-d-aspartate antagonists indicates an important role for this spinal receptor in regulating hyperalgesic states induced by tissue injury and inflammation and reveals an action that is distinct from those observed with other glutamate receptor antagonists.

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