Yamamoto Tatsuo, Kozikowski Alan, Zhou Jia, Neale Joseph H
Department of Biology, Georgetown University, Washington, DC 20057, USA.
Mol Pain. 2008 Aug 1;4:31. doi: 10.1186/1744-8069-4-31.
The peptide neurotransmitter N-Acetylaspartylglutamate (NAAG) is the third most prevalent transmitter in the mammalian central nervous system. Local, intrathecal and systemic administration of inhibitors of enzymes that inactivate NAAG decrease responses to inflammatory pain in rat models. Consistent with NAAG's activation of group II metabotropic glutamate receptors, this analgesia is blocked by a group II antagonist.
This research aimed at determining if analgesia obtained following systemic administration of NAAG peptidase inhibitors is due to NAAG activation of group II mGluRs in brain circuits that mediate perception of inflammatory pain. NAAG and NAAG peptidase inhibitors, ZJ43 and 2-PMPA, were microinjected into a lateral ventricle prior to injection of formalin in the rat footpad. Each treatment reduced the early and late phases of the formalin-induced inflammatory pain response in a dose-dependent manner. The group II mGluR antagonist reversed these analgesic effects consistent with the conclusion that analgesia was mediated by increasing NAAG levels and the peptide's activation of group II receptors.
These data contribute to proof of the concept that NAAG peptidase inhibition is a novel therapeutic approach to inflammatory pain and that these inhibitors achieve analgesia by elevating synaptic levels of NAAG within pain processing circuits in brain.
肽类神经递质N-乙酰天冬氨酰谷氨酸（NAAG）是哺乳动物中枢神经系统中第三大普遍存在的递质。在大鼠模型中，局部、鞘内和全身给予使NAAG失活的酶的抑制剂可降低对炎性疼痛的反应。与NAAG对II组代谢型谷氨酸受体的激活作用一致，这种镇痛作用可被II组拮抗剂阻断。
本研究旨在确定全身给予NAAG肽酶抑制剂后获得的镇痛作用是否归因于NAAG对介导炎性疼痛感知的脑回路中II组代谢型谷氨酸受体的激活。在大鼠足垫注射福尔马林之前，将NAAG以及NAAG肽酶抑制剂ZJ43和2-PMPA微量注射到侧脑室。每种处理均以剂量依赖性方式降低了福尔马林诱导的炎性疼痛反应的早期和晚期阶段。II组代谢型谷氨酸受体拮抗剂逆转了这些镇痛作用，这与镇痛作用是通过提高NAAG水平以及该肽对II组受体的激活介导的这一结论一致。
这些数据有助于证明NAAG肽酶抑制是一种治疗炎性疼痛的新方法，并且这些抑制剂通过提高脑内疼痛处理回路中NAAG的突触水平来实现镇痛。
