Chloride cation co-transporters and hyperalgesic states

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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.