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，即在导致继发性痛觉过敏的条件下，初级传入去极化（PAD）的正常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，背根反射（DRR）逆向和顺向传导，引起A β纤维诱发的疼痛。该过程被认为是由阳离子氯共转运蛋白NKCC 1调节的GABA能机制介导的，NKCC 1在感觉神经元中维持高的细胞内Cl-浓度，从而改变GABA-A受体通道的Cl-逆转电位。我们建议通过以下假设来评估NKCC 1表达和/或活性的改变调节炎性疼痛状态中PAD向DRR的转化的假设：1）伤害感受性DRG神经元表达NKCC 1，2）NKCC 1蛋白的增加伴随炎性痛觉过敏的发展，3）NKCC 1功能的增加和/或或炎症后的表达导致GABA-A介导的感觉传入反应的电生理学改变。这些假设包括一个综合的系列研究，全面测试有关继发性痛觉过敏的假设，导致可能的治疗策略，减轻炎症性疼痛。

DESCRIPTION (provided by applicant): The sponsor's laboratory has developed the novel hypothesis that under conditions that lead to secondary hyperalgesia, the normal A(-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) which conduct both antidromically and orthodromically causing A(-fiber evoked pain. This process is proposed to be mediated by GABAergic mechanisms regulated by the cation chloride co-transporter NKCC1, which maintains a high intracellular CI- concentration in sensory neurons thereby altering the CI- reversal potential of GABA-A receptor channels. We propose to evaluate the hypothesis that alterations in NKCC1 expression and/or activity regulate the conversion of PAD to DRR in inflammatory pain states through the following hypothesis: 1) that nociceptive DRG neurons express NKCC1, 2) that increases in NKCC1 protein accompany the development of inflammatory hyperalgesia and 3) that increases in NKCC1 function and/or expression after inflammation lead to electrophysiological alterations in GABA-A mediated sensory afferent responses. These hypotheses comprise an integrated series of studies that comprehensively test hypotheses concerning secondary hyperalgesia leading to possible therapeutic strategies for the alleviation of inflammatory pain.