Local administration of N-acetylaspartylglutamate (NAAG) peptidase inhibitors is analgesic in peripheral pain in rats
Local administration of N-acetylaspartylglutamate (NAAG) peptidase inhibitors is analgesic in peripheral pain in rats
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DOI：
10.1111/j.1460-9568.2006.05272.x
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发表时间：
2007-01-01
影响因子：
3.4
通讯作者：
Neale, Joseph H.
中科院分区：
文献类型：
--
作者：
Yamamoto, Tatsuo;Saito, Osamu;Neale, Joseph H.
肽神经递质N-乙酰基谷氨酸（NAAG）选择性激活II组代谢型谷氨酸受体（mGluR）。在炎症性和神经性疼痛的大鼠模型中，全身给予抑制NAAG的酶的抑制剂导致疼痛反应降低。这些作用被II组mGluR拮抗剂阻断。这项研究验证了这样的假设：NAAG肽酶抑制的一些镇痛作用是由NAAG作用于炎症部位的感觉神经突mGluRs介导的。第二组mGluR激动剂，SLx-3095-1，NAAG和APDC，或NAAG肽酶抑制剂，ZJ-43和2-PMPA，注射到大鼠足垫减少角叉菜胶或福尔马林模型中的疼痛反应。SLx-3095-1、APDC、ZJ-43、2-PMPA和NAAG的镇痛作用可被选择性II组mGluR拮抗剂LY 341495阻断。将第II组mGluR激动剂、NAAG或肽酶抑制剂注射到对侧大鼠足垫中对注射爪的疼痛感知没有影响。在10-100 μ M时，ZJ-43和2-PMPA对mGluR 2或mGluR 3没有表现出一致的激动剂活性。与外周给药NAAG肽酶抑制剂通过从外周感觉神经突释放的NAAG增加mGluR 3的活化的结论一致，我们发现在未刺激的大鼠后爪中NAAG的组织平均浓度为约6 μ M。这些数据扩展了我们对这种肽在感觉神经元中的作用的理解，并揭示了通过局部应用NAAG肽酶抑制剂治疗炎性疼痛的潜力，其剂量可能很少或没有中枢神经系统作用。
The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) selectively activates group II metabotropic glutamate receptors (mGluRs). Systemic administration of inhibitors of the enzymes that inactivate NAAG results in decreased pain responses in rat models of inflammatory and neuropathic pain. These effects are blocked by a group II mGluR antagonist. This research tested the hypothesis that some analgesic effects of NAAG peptidase inhibition are mediated by NAAG acting on sensory neurite mGluRs at the site of inflammation. Group II mGluR agonists, SLx-3095-1, NAAG and APDC, or NAAG peptidase inhibitors, ZJ-43 and 2-PMPA, injected into the rat footpad reduced pain responses in carrageenan or formalin models. The analgesic effects of SLx-3095-1, APDC, ZJ-43, 2-PMPA and NAAG were blocked by co-injection of LY341495, a selective group II mGluR antagonist. Injection of group II mGluR agonists, NAAG or the peptidase inhibitors into the contralateral rat footpad had no effect on pain perception in the injected paw. At 10-100 mu M ZJ-43 and 2-PMPA demonstrated no consistent agonist activity at mGluR2 or mGluR3. Consistent with the conclusion that peripherally administered NAAG peptidase inhibitors increase the activation of mGluR3 by NAAG that is released from peripheral sensory neurites, we found that the tissue average concentration of NAAG in the unstimulated rat hind paw was about 6 mu M. These data extend our understanding of the role of this peptide in sensory neurons and reveal the potential for treatment of inflammatory pain via local application of NAAG peptidase inhibitors at doses that may have little or no central nervous system effects.