Chloride cation co-transporters and hyperalgesic states

描述(由申请人提供)：赞助商的实验室提出了一项新的假设，即在导致触摸诱发痛觉异常的条件下，初级传入去极化(PAD)的正常抑制性Aβ纤维诱导转化为初级传入伤害性感受器的兴奋，导致背根反射(DRR)的产生。然后，这些DRRs既逆行传导，引起血管扩张，又顺行传导，引起Aβ纤维诱发的疼痛。这一过程被认为是由阳离子-氯共转运体NKCC1调节的GABA能机制所介导的。NKCC1在感觉神经元中维持较高的细胞内氯浓度，从而导致通过GABA-A通道以负电位向外流动氯离子，从而导致去极化。NKCC1表达和/或活性的增加将进一步增强这种电化学梯度，导致这些神经元中GABA-A介导的去极化增加。我们认为在角叉菜胶炎症模型中，NKCC1表达和/或活动的改变调节初级传入去极化向背根反射的转换，这一假说是通过以下假设来评价的：1)伤害性DRG神经元表达NKCC1，NKCC1蛋白存在于这些神经元的中央终末。2)在角叉菜胶诱导的炎症过程中，DRG神经元及其中枢终末NKCC1蛋白和/或活性增加。3)角叉菜胶处理后NKCC1表达和/或活性的增加导致GABA-A介导的感觉传入反应的电生理改变。这些假说由一系列综合的研究组成，这些研究测试了有关Abeta纤维驱动的疼痛的假说，从而得出了可能的减轻炎症性疼痛的治疗策略。

DESCRIPTION (provided by applicant): The sponsor's laboratory has developed the novel hypothesis that under conditions that lead to touch-evoked allodynia, the normal inhibitory Abeta-fiber induction of primary afferent depolarization (PAD) is converted to an excitation of primary afferent nociceptors leading to the production of dorsal root reflexes (DRR). These DRRs would then conduct both antidromically, causing vasodilatation, and orthodromically, causing Abeta-fiber evoked pain. This process is proposed to be mediated by GABAergic mechanisms regulated by the cation-chloride cotransporter NKCC1. NKCC1 maintains a high intracellular chloride concentration in sensory neurons thereby causing an outward chloride flow at negative potentials through GABA-A channels leading to depolarization. Increases in NKCC1 expression and/or activity would further augment this electro-chemical gradient leading to an increase in GABA-A-mediated depolarization in these neurons. We propose to evaluate the hypothesis that alterations in NKCC1 expression and/or activity regulate the conversion of primary afferent depolarization to dorsal root reflexes in the carrageenan inflammation model through the following hypothesis: 1) That nociceptive DRG neurons express NKCC1 and NKCC1 protein is present in the central terminals of these neurons. 2) That increases in NKCC1 protein and/or activity in DRG neurons and their central terminals accompany the development of carrageenan-induced inflammation. 3) That increases in NKCC1 expression and/or activity after carrageenan treatment lead to electrophysiological alterations in GABA-A-mediated sensory afferent responses. These hypotheses comprise an integrated series of studies that test hypotheses concerning Abeta-fiber driven pain leading to possible therapeutic strategies for the alleviation of inflammatory pain.