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.
|Price, Theodore J; Cervero, Fernando; Gold, Michael S et al. (2009) Chloride regulation in the pain pathway. Brain Res Rev 60:149-70|
|Price, Theodore J; Rashid, Md Harunor; Millecamps, Magali et al. (2007) Decreased nociceptive sensitization in mice lacking the fragile X mental retardation protein: role of mGluR1/5 and mTOR. J Neurosci 27:13958-67|
|Price, Theodore J; Flores, Christopher M (2007) Critical evaluation of the colocalization between calcitonin gene-related peptide, substance P, transient receptor potential vanilloid subfamily type 1 immunoreactivities, and isolectin B4 binding in primary afferent neurons of the rat and mouse. J Pain 8:263-72|
|Pitcher, Mark H; Price, Theodore J; Entrena, Jose M et al. (2007) Spinal NKCC1 blockade inhibits TRPV1-dependent referred allodynia. Mol Pain 3:17|
|Price, Theodore J; Hargreaves, Kenneth M; Cervero, Fernando (2006) Protein expression and mRNA cellular distribution of the NKCC1 cotransporter in the dorsal root and trigeminal ganglia of the rat. Brain Res 1112:146-58|
|Price, T J; Flores, C M; Cervero, F et al. (2006) The RNA binding and transport proteins staufen and fragile X mental retardation protein are expressed by rat primary afferent neurons and localize to peripheral and central axons. Neuroscience 141:2107-16|
|Price, Theodore J; Cervero, Fernando; de Koninck, Yves (2005) Role of cation-chloride-cotransporters (CCC) in pain and hyperalgesia. Curr Top Med Chem 5:547-55|