Intracerebroventricular administration of N-acetylaspartylglutamate (NAAG) peptidase inhibitors is analgesic in inflammatory pain
Intracerebroventricular administration of N-acetylaspartylglutamate (NAAG) peptidase inhibitors is analgesic in inflammatory pain
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DOI：
10.1186/1744-8069-4-31
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发表时间：
2008-08-01
期刊：
影响因子：
3.3
通讯作者：
Neale, Joseph H.
中科院分区：
文献类型：
--
作者：
Yamamoto, Tatsuo;Kozikowski, Alan;Neale, Joseph H.
肽神经递质n -乙酰天冬氨酸谷氨酸（NAAG）是哺乳动物中枢神经系统中第三大常见递质。在大鼠模型中，局部、鞘内和全身给药使NAAG失活的酶抑制剂可降低对炎症性疼痛的反应。与NAAG激活II组代谢性谷氨酸受体一致，这种镇痛作用被II组拮抗剂阻断。结果：本研究旨在确定全身给予NAAG肽酶抑制剂后获得的镇痛是否由于NAAG激活了介导炎症性疼痛感知的脑回路中的II组mGluRs。在足垫注射福尔马林之前，将NAAG和NAAG肽酶抑制剂ZJ43和2PMPA微量注射到大鼠侧脑室。每种治疗都以剂量依赖的方式减少了福尔马林诱导的炎症性疼痛反应的早期和晚期。II组mGluR拮抗剂逆转了这些镇痛作用，这与NAAG水平升高和II组受体激活肽介导镇痛的结论一致。结论：这些数据有助于证明NAAG肽酶抑制是一种治疗炎症性疼痛的新方法，这些抑制剂通过提高大脑疼痛处理回路中NAAG的突触水平来实现镇痛。
Background: 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.Results: 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 2PMPA, 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.Conclusion: 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.