Vector-mediated release of GABA attenuates pain-related behaviors and reduces Na(V)1.7 in DRG neurons.
Vector-mediated release of GABA attenuates pain-related behaviors and reduces Na(V)1.7 in DRG neurons.
复制标题
DOI：
10.1016/j.ejpain.2011.03.007
复制
发表时间：
2011-10
期刊：
影响因子：
--
通讯作者：
Fink DJ
中科院分区：
文献类型：
--
作者：
Chattopadhyay M;Mata M;Fink DJ
疼痛是糖尿病并发症神经病变的常见和衰弱的伴随症状。在目前的研究中，我们研究了在疼痛性糖尿病神经病变（PDN）大鼠模型中，利用基于非复制性单纯疱疹病毒（HSV）的载体（vG）将谷氨酸脱羧酶（GAD67）基因转移到体内背根神经节（DRG），从而实现γ氨基丁酸（GABA）持续释放的影响。皮下接种vG可减轻PDN大鼠的机械性痛觉过敏、热痛觉过敏和冷异常性痛。在体内，从载体转导的细胞中持续释放GABA阻止了PDN特征的电压门控钠通道异构体1.7 （NaV1.7）蛋白的增加。在体外，用vG感染原代DRG神经元可以阻止高血糖导致的NaV1.7升高。载体介导的GABA对体外NaV1.7水平的影响可被苯氯芬阻断，但不能被双库兰阻断，这是一种GABAB受体效应，可被百日咳毒素（PTX）干扰Gα(i/o)功能所阻断。结合我们之前的观察，通过载体介导的脑啡肽释放持续激活δ阿片受体也可以阻止体外或体内暴露于高血糖的DRG中NaV1.7的增加，本报告的观察结果表明，DRG神经元中G蛋白偶联受体（GPCR）的激活调节初级传入神经的表型是一种新的共同机制。
Pain is a common and debilitating accompaniment of neuropathy that occurs as a complication of diabetes. In the current study, we examined the effect of continuous release of gamma amino butyric acid (GABA), achieved by gene transfer of glutamic acid decarboxylase (GAD67) to dorsal root ganglia (DRG) in vivo using a nonreplicating herpes simplex virus (HSV)-based vector (vG) in a rat model of painful diabetic neuropathy (PDN). Subcutaneous inoculation of vG reduced mechanical hyperalgesia, thermal hyperalgesia and cold allodynia in rats with PDN. Continuous release of GABA from vector transduced cells in vivo prevented the increase in the voltage gated sodium channel isoform 1.7 (NaV1.7) protein that is characteristic of PDN. In vitro, infection of primary DRG neurons with vG prevented the increase in NaV1.7 resulting from exposure to hyperglycemia. The effect of vector-mediated GABA on NaV1.7 levels in vitro was blocked by phaclofen but not by bicuculline, a GABAB receptor effect that was blocked by pertussis toxin-(PTX) interference with Gα(i/o) function. Taken in conjunction with our previous observation that continuous activation of delta opioid receptors by vector-mediated release of enkephalin also prevents the increase in NaV1.7 in DRG exposed to hyperglycemia in vitro or in vivo, the observations in this report suggest a novel common mechanism through which activation of G protein coupled receptors (GPCR) in DRG neurons regulate the phenotype of the primary afferent.
登录
查看更多内容
DOI：
10.1016/j.bbrc.2005.11.057
发表时间：
2006-01-13
影响因子：
3.1
作者：
Hong, SS;Wiley, JW
通讯作者：
Wiley, JW
影响因子：
4
作者：
Devor, M
通讯作者：
Devor, M
影响因子：
11.2
作者：
Hao, SG;Mata, M;Fink, DJ
通讯作者：
Fink, DJ
影响因子：
7.4
作者：
Finnerup, Nanna Brix;Sindrup, Soren Hein;Jensen, Troels Staehelin
通讯作者：
Jensen, Troels Staehelin
影响因子：
2.8
作者：
Eaton, MJ;Plunkett, JA;Montanez, K
通讯作者：
Montanez, K