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.
