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Type 2 diabetes affects 9% of the United States population and a substantial portion of diabetic patients experience pain resulting from peripheral and central neuronal dysfunction. Painful diabetic neuropathy is initiated by chronic hyperglycemia-induced neurotoxicity that results in maladaptive sensory processing manifesting in allodynia, hypersensitivity to pressure and thermal stimuli, and spontaneous pain such as burning, aching, and paresthesias. Preclinical research into the central and peripheral mechanisms of chronic spontaneous pain in type 2 diabetes is lacking. Therefore I will use the Zucker Diabetic Fatty rat model of type 2 diabetes to assess the mechanisms of spontaneous pain using conditioned place preference behavior, western blotting, immunohistochemistry, and calcium imaging. My overall hypothesis is that hypersensitivity resulting from increased calcium signaling and extracellular signal-regulated kinase activation are reversed by pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma (PPARã). Insulin insensitivity leads to a chronic elevation of blood glucose, which results in an increase in glucose metabolites such as methylglyoxal. Methylglyoxal has recently been shown to potentiate the non-selective cation channel TRPA1 and the sodium channel NAV1.8, which are highly expressed on peripheral nociceptors and contribute to hypersensitivity in preclinical pain models. After peripheral nerve injury pioglitazone reduces behavioral hypersensitivity and neuronal sensitization in the form of decreased ERK activation. Similarly, pioglitazone attenuates nerve microvasculature dysfunction induced by glucose neurotoxicity and alleviates high circulating levels of methylglyoxal. My long-term goals are to determine the peripheral and central mechanisms of chronic pain in type 2 painful diabetic neuropathy.
|Effective start/end date||4/1/13 → 3/31/15|
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