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首页> 外文期刊>The European Journal of Neuroscience >Antinociceptive effects of N-acetylaspartylglutamate (NAAG) peptidase inhibitors ZJ-11, ZJ-17 and ZJ-43 in the rat formalin test and in the rat neuropathic pain model.
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Antinociceptive effects of N-acetylaspartylglutamate (NAAG) peptidase inhibitors ZJ-11, ZJ-17 and ZJ-43 in the rat formalin test and in the rat neuropathic pain model.

机译：N-乙酰天门冬氨酸谷氨酸（NAAG）肽酶抑制剂ZJ-11，ZJ-17和ZJ-43在大鼠福尔马林测试和大鼠神经性疼痛模型中的镇痛作用。

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Abstract The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) acts as an agonist at group II metabotropic glutamate receptors (mGluRs). NAAG is inactivated by extracellular peptidase activity yielding glutamate and N-acetylaspartate. We recently developed a series of potent NAAG peptidase inhibitors, including ZJ-11, ZJ-17 and ZJ-43. In the present study, we examined the effects of intrathecally administered ZJ-11 and ZJ-17 and intravenously administered ZJ-11 and ZJ-43 in the rat formalin test (an inflammatory pain model) and in the rat partial sciatic nerve ligation model (a neuropathic pain model). Intrathecal injection of ZJ-11 or ZJ-17 or intravenous injection of ZJ-11 or ZJ-43 suppressed both phases of the agitation behaviour induced by paw formalin injection. Intrathecal and intravenous injection of ZJ-11 suppressed the expression of Fos-like immunoreactivity, induced by paw formalin injection, in laminae I-II in segments L4-L5 of the spinal cord, suggesting an action on sensory spinal transmission. Partial sciatic nerve ligation induced significant mechanical allodynia 7 days after the nerve injury. Intrathecal injection of ZJ-11 or ZJ-17 or intravenous administration of ZJ-11 or ZJ-43 attenuated the level of mechanical allodynia induced by this nerve ligation. These effects of intrathecally or intravenously administered ZJ compounds in both the formalin test and the partial sciatic nerve ligation model were completely antagonized by pretreatment with LY-341495, a highly selective group II mGluR antagonist. Thus, elevation of extracellular NAAG, induced by the inhibition of NAAG peptidase, activates group II mGluRs and produces an analgesic effect in neuropathic and inflammatory and pain models. In contrast, peptidase inhibition did not affect the threshold for withdrawal from a noxious mechanical stimulus or from an acute thermal stimulus in the hotplate test.
机译：摘要肽神经递质N-乙酰天冬氨酰谷氨酸（NAAG）在II型代谢型谷氨酸受体（mGluRs）中起激动剂的作用。通过细胞外肽酶活性使NAAG失活，从而产生谷氨酸和N-乙酰天门冬氨酸。我们最近开发了一系列有效的NAAG肽酶抑制剂，包括ZJ-11，ZJ-17和ZJ-43。在本研究中，我们研究了在大鼠福尔马林测试（炎性疼痛模型）和大鼠部分坐骨神经结扎模型（鞘内注射）中，鞘内施用ZJ-11和ZJ-17以及静脉内施用ZJ-11和ZJ-43的效果神经性疼痛模型）。鞘内注射ZJ-11或ZJ-17或静脉注射ZJ-11或ZJ-43抑制了爪福尔马林注射诱导的两个阶段的搅拌行为。鞘内和静脉内注射ZJ-11抑制了爪福尔马林注射诱导的脊髓层L4-L5的层I-II中Fos样免疫反应性的表达，表明对感觉脊髓的传递有作用。神经损伤后7天，部分坐骨神经结扎引起明显的机械性异常性疼痛。鞘内注射ZJ-11或ZJ-17或静脉内施用ZJ-11或ZJ-43可减轻由这种神经结扎引起的机械性异常性疼痛的水平。在福尔马林试验和部分坐骨神经结扎模型中，鞘内或静脉内施用ZJ化合物的这些作用通过用高度选择性的II类mGluR拮抗剂LY-341495预处理而完全被拮抗。因此，通过抑制NAAG肽酶诱导的细胞外NAAG的升高激活了II类mGluRs，并在神经性和炎性及疼痛模型中产生了镇痛作用。相反，肽酶抑制不影响在热板试验中从有害机械刺激或从急性热刺激退出的阈值。

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