The Effect of Intrathecal ACEA 1021, Competitive Glycine-site NMDA Receptor Antagonist on the Hyperalgesia Observed after Thermal Injury in the Rat

Jun, Jong Hun; Cho, Sung Ho; Nam, Sang Beom; Cho, Sang Yoon; Shin, Woo Jong; Kim, Dong Won; Kim, Kyo Sang

Abstract

BACKGROUND: Previous reports have described NMDA antagonist reduced the nerve injury induced or inflammatory thermal hyperalgesia. One of the peculiarities of the NMDA receptor is the requirement for glycine as the co-agonist in order to be activated. Thus, the function of NMDA receptors can be modulated by ligands acting as agonists or antagonists at the glycine co-agonist site. ACEA 1021 has been recently characterized as a high potency competitive NMDA receptor/glycine site antagonist. This study evaluated the effects of spinally administered ACEA 1021 on the thermal hyperalgesia state induced by mild burn.
METHODS
Rats were prepared with chronic spinal catheters. A thermal injury was induced after briefly anesthetizing with halothane, by applying the left hind paw to a thermal surface (52.5oC) for 45 sec. This exposure results in a mild erythema, but no blistering. Thermal escape latency of the hind paw was determined using an underglass thermal stimulus with which response latencies of the injured and uninjured (normal) paw could be obtained. In this work, ACEA 1021 was injected through intrathecal catheters in rats with mild burn injury on the right hindpaw, after then paw withdrawal latency was measured in both hindpaw every 30 minute for 3 hours.
RESULTS
The intrathecal injection of ACEA 1021 (2.4-24 microgram) produced a dose dependent reversal of the hyperalgesia in the right hindpaw, but had no effect upon the response latency of the normal left hind paw even at the largest doses. The effects of intrathecal ACEA 1021 on the hyperalgesia reversed by intrathecal D-serine.
CONCLUSIONS
Intrathecal ACEA 1021, competitive-glycine site NMDA receptor antagonist produce a dose-dependent inhibition and D-serine-sensitive reversal of the thermal hyperalgesia evoked mild burn injury. These results suggested that the glycine site of spinal NMDA receptor play an important role in the hyperalgesia induced by mild burn injury.