Site-specific increases in peripheral cannabinoid receptors and their endogenous ligands in a model of neuropathic pain
Site-specific increases in peripheral cannabinoid receptors and their endogenous ligands in a model of neuropathic pain
复制标题
DOI：
10.1016/j.pain.2006.06.016
复制
发表时间：
2006-12-15
期刊：
影响因子：
7.4
通讯作者：
Spigelman, Igor
中科院分区：
文献类型：
--
作者：
Mitrirattanakul, Somsak;Ramakul, Navapoln;Spigelman, Igor
外周大麻素受体1（CB 1 R）的选择性激活已被证明可以抑制啮齿动物的神经性疼痛症状。然而，相对知之甚少的CB 1 R及其内源性配体的发展或维持神经性疼痛过程中的变化。采用免疫组织化学、Western blot、实时荧光定量逆转录聚合酶链反应（real-time reverse transcriptionpolymerase chain reaction，RT-PCR）和液相色谱/质谱（liquid chromatography/mass spectrometry，L5）等方法，研究了大鼠腰段（L4和L5）背根神经节（dorsal root ganglia，DRG）内CB（1）Rs和内源性大麻素N-花生四烯酰乙醇胺（N-arachidonoylethanolamine/anandamide，AEA）及2-花生四烯酰甘油（2-arachidonoylglycerol，2-AG）在神经病理性疼痛诱导（L5 spinal nerve ligation：SNL）后的变化。免疫组织化学显示，在对照组大鼠中，CB 1 R在大多数（76-83%）伤害感受神经元中表达，如与异凝集素B4（1B 4）或识别瞬时受体电位香草酸（TRPV 1）、降钙素基因相关肽（CGRP）和N-甲基-D-天冬氨酸受体的NR 2C/2D亚基的抗体共标记所示。L5 SNL后，同侧未损伤的L4 DRG中CB 1 R mRNA和蛋白增加，而L4和L5 DRG中CB 1 R免疫反应（CB 1 R-ir）神经元的百分比保持不变。然而，对于这些CB 1 R-ir神经元，我们观察到同侧L4 DRG中TRPVI-ir细胞的百分比显著增加，而同侧L5 DRG中IB 4和CGRP共标记细胞的百分比减少。AEA和2-AG水平仅在同侧L5 DRG中显著增加。这些结果与大麻素在神经性疼痛中保留的镇痛作用一致，并为开发基于外周作用的内源性大麻素的神经性疼痛治疗干预提供了合理的框架。(c)2006年国际疼痛研究协会。Elsevier B. V.出版，保留所有权利。
Selective activation of the peripheral cannabinoid receptor 1 (CB1R) has been shown to suppress neuropathic pain symptoms in rodents. However, relatively little is known about changes in CB1R and its endogenous ligands during development or maintenance of neuropathic pain. Using immunohistochemistry, Western blot, real-time reverse transcription polymerase chain reaction, as well as liquid chromatography/mass spectrometry, we studied the changes in CB(1)Rs and endocannabinoids N-arachidonoylethanolamine/anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in rat lumbar (L4 and L5) dorsal root ganglia (DRG) after neuropathic pain induction (L5 spinal nerve ligation: SNL). Immunohistochemistry revealed that in control rats, CB1R is expressed in the majority (76-83%) of nociceptive neurons as indicated by co-labeling with isolectin B4 (1B4) or antibodies recognizing transient receptor potential vanilloid (TRPV1), calcitonin gene related peptide (CGRP), and the NR2C/2D subunits of the N-methyl-D-aspartate receptor. After L5 SNL, CB1R mRNA and protein increases in the ipsilateral uninjured L4 DRG whereas the percentages of CB1R immunoreactive (CB1R-ir) neurons remain unchanged in L4 and L5 DRG. However, for these CB1R-ir neurons, we observe significant increases in percentage of TRPVI-ir cells in ipsilateral L4 DRG, and decreases in percentage of IB4- and CGRP-co-labeled cells in ipsilateral L5 DRG. Levels of both AEA and 2-AG increase significantly only in the ipsilateral L5 DRG. These results are consistent with the preserved analgesic effects of cannabinoids in neuropathic pain and provide a rational framework for the development of peripherally acting endocannabinoid-based therapeutic interventions for neuropathic pain. (c) 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.