Endogenous N-acetylaspartylglutamate (NAAG) inhibits synaptic plasticity/transmission in the amygdala in a mouse inflammatory pain model
Endogenous N-acetylaspartylglutamate (NAAG) inhibits synaptic plasticity/transmission in the amygdala in a mouse inflammatory pain model
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DOI：
10.1186/1744-8069-6-60
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发表时间：
2010-09-22
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：
Adedoyin, Mary O.;Vicini, Stefano;Neale, Joseph H.
背景：神经递质n -乙酰天冬氨酸（NAAG）肽在整个脊椎动物神经系统中广泛表达，包括疼痛处理神经轴。NAAG肽酶抑制剂在动物疼痛模型中具有镇痛作用。然而，参与NAAG镇痛作用的脑区尚未得到严格定义。II组代谢性谷氨酸受体（mGluR2/3）在杏仁核中央（CeLC）外囊部分的疼痛加工中起作用。鉴于杏仁核中NAAG的高浓度及其激活II组mGluR(mGluR(3) > mGluR(2))，本研究采用小鼠炎症性疼痛福尔马林模型来验证NAAG影响杏仁核疼痛加工的假设。研究了小鼠脊髓旁杏仁核传入神经刺激后CeLC神经元的诱发兴奋性突触后电流（eEPSCs）。结果：NAAG肽酶抑制剂ZJ43的剂量依赖性抑制了对照CeLC中eEPSCs的振幅高达50%，表明NAAG在调节该突触的兴奋性传递中起作用。II组mGluR激动剂（SLx-3095-1）同样抑制了约30%的eEPSC振幅。这两种作用都被II组mGluR拮抗剂LY341495阻断。ZJ43在炎症24小时后减少eEPSCs的效果远不如SLx，这表明炎症诱导NAAG释放减少或mGluR(2)与mGluR(3)表达比例增加。在炎症发生时间近端全身注射ZJ43阻断了24小时后外周炎症诱导的该通路突触传递的增加，并阻断了该时间点发生的机械异常性痛的诱导。结论：本研究的主要发现是NAAG和NAAG肽酶抑制降低了中央杏仁核疼痛加工通路中棘旁臂突触的兴奋性神经传递和炎症诱导的可塑性。
Background: The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is widely expressed throughout the vertebrate nervous system, including the pain processing neuraxis. Inhibitors of NAAG peptidases are analgesic in animal models of pain. However, the brain regions involved in NAAG's analgesic action have not been rigorously defined. Group II metabotropic glutamate receptors (mGluR2/3) play a role in pain processing in the laterocapsular part of the central nucleus of the amygdala (CeLC). Given the high concentration of NAAG in the amygdala and its activation of group II mGluRs (mGluR(3) > mGluR(2)), this study was undertaken using the mouse formalin model of inflammatory pain to test the hypothesis that NAAG influences pain processing in the amygdala. Evoked excitatory postsynaptic currents (eEPSCs) were studied in neurons in the CeLC of mouse brain slices following stimulation of the spinoparabrachial amygdaloid afferents.Results: Application of a NAAG peptidase inhibitor, ZJ43, dose dependently inhibited the amplitude of the eEPSCs by up to 50% in control CeLC demonstrating the role of NAAG in regulation of excitatory transmission at this synapse. A group II mGluR agonist (SLx-3095-1) similarly inhibited eEPSC amplitude by about 30%. Both effects were blocked by the group II mGluR antagonist LY341495. ZJ43 was much less effective than SLx in reducing eEPSCs 24 hours post inflammation suggesting an inflammation induced reduction in NAAG release or an increase in the ratio of mGluR(2) to mGluR(3) expression. Systemic injection of ZJ43 proximal to the time of inflammation blocked peripheral inflammation-induced increases in synaptic transmission of this pathway 24 hrs later and blocked the induction of mechanical allodynia that developed by this time point.Conclusions: The main finding of this study is that NAAG and NAAG peptidase inhibition reduce excitatory neurotransmission and inflammation-induced plasticity at the spinoparabrachial synapse within the pain processing pathway of the central amygdaloid nucleus.