Agmatine is Enhanced by NMDA Receptor Antagonist in Formalin-induced Pain

Objectives: Agmatine is an endogenous substance synthesized from L-arginine and is widely localized in the CNS. And, this substance could regulate various systems including excitatory glutamatergic nervous system excessive activation of the N-methyl-D-aspartate (NMDA) receptor related to nitric oxide (NO) production system. Hyperalgesia caused by peripheral tissue damage is involved in glutamate related neuronal plasticity of the spinal cord. However, its mechanism of action is still unknown. Therefore, we determined the analgesic effect of agmatine in relation to modification of glutamate related neuronal　plasticity using a rat inflammatory pain model. Methods: SD rats implanted with intrathecal catheter were subjected for formalin-induced hyperalgesia. The pain behavior was assessed by spontaneous flinches per min after formalin paw injection under halothane anesthesia. The rats were divided into seven groups as follows, 1) Non-treated(saline, it. inj.), 2)Agmatine( 30ug, it. inj.), 3) MK-801(15ug, it. inj.), 4) AVS(OH radical scavenger, 100ug, it. inj), 5) Agmatine+ MK-801, 6) Agmatine + AVS. Results: Rats showed biphasic pain behavior, sum of the first(0-5min) are 14/min and sum of the second(20-60min) are 147/min. All drugs attenuated sum of the second phase from 32 to 68 % compared with non-treated but did not the first phase. Additive effect of agmatine with MK-801 was obtained but did not with AVS. Conclusion: Based on the present study we suggest that synergistic analgesia effect of agmatine may involve the inhibition of NMDA receptor related to the NO production, suggesting this agmatine acts on multi-site of glutamatergic neuronal activation in developing hyperalgesia.