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. ? ?
|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|