Chloride cation co-transporters and hyperalgesic states

描述（由申请方提供）：申办方的实验室已经开发了一种新的假设，即在导致触摸诱发异常性疼痛的条件下，初级传入去极化（PAD）的正常抑制性A β纤维诱导转化为初级传入伤害感受器的兴奋，导致背根反射（DRR）的产生。然后，这些DRR会逆向传导，引起血管舒张，并顺向传导，引起A β纤维诱发的疼痛。这一过程被认为是由阳离子-氯离子协同转运蛋白NKCC 1调控的GABA能机制介导的。NKCC 1在感觉神经元中维持高细胞内氯离子浓度，从而在负电位下通过GABA-A通道引起向外氯离子流，导致去极化。NKCC 1表达和/或活性的增加将进一步增加这种电化学梯度，导致这些神经元中GABA-A介导的去极化增加。我们建议通过以下假设来评估在角叉菜胶炎症模型中NKCC 1表达和/或活性的改变调节初级传入去极化向背根反射的转换的假设：1）伤害性DRG神经元表达NKCC 1并且NKCC 1蛋白存在于这些神经元的中枢终末。2)NKCC 1蛋白和/或活性在DRG神经元及其中枢终末的增加伴随角叉菜胶诱导的炎症的发展。3)角叉菜胶处理后NKCC 1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。这些假设包括一系列综合研究，这些研究测试了关于A β-纤维驱动疼痛的假设，从而为缓解炎症性疼痛提供了可能的治疗策略。

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.