Diabetic neuropathy is a widespread clinical problem for which there is no FDA-approved, mechanistically based treatment and is predicted to develop in over half of the approximately 20 million people currently afflicted by diabetes mellitus in the USA. A significant proportion of both insulin-deficient (type 1) and insulin- resistant (type 2) diabetic patients complain of pain or paresthesias that impair quality of life. The etiology of painful diabetic neuropathy is not known and current treatment strategies are limited to drugs with ill-defined mechanisms of action and with side effect profiles that impede normal daily functions and limit effective dosing. Diabetic rats develop hyperalgesia in response to paw formalin injection and allodynia in response to light touch, and they are widely used to model painful diabetic neuropathy in both mechanistic and drug efficacy studies. Recent findings have implicated spinal oligodendrocytes as a site of a pathogenic lesion that initiates spinally mediated hyperalgesia in diabetes. The pathogenic mechanism involves metabolism of excess glucose by aldose reductase, located exclusively in spinal oligodendrocytes, and the subsequent up-regulation of cyclooxygenase 2 (COX-2) in spinal oligodendrocytes and/or neurons. We propose to define the cellular mechanisms by which glucose metabolism by aldose reductase induces COX-2 expression and activity and also the inter-cellular mechanisms that allow oligodendrocytes to initiate spinal hyperalgesa. This will be accomplished by applying a combination of cellular, biochemical and pharmacological techniques to in vitro studies using mature oligodendrocytes derived from the spinal cord of adult normal and diabetic rats. We also intend to investigate pathogenic mechanisms underlying tactile allodynia and formalin-evoked hyperalgesia in diabetic rats that are not related to spinal aldose reductase and COX-2 activity. We will address the hypothesis that decreased expression of the KCC2 cation cotransporter converts spinal GABAergic pathways from inhibitory to excitatory to promote tactile allodynia. The role of altered primary afferent BDNF production in inducing altered spinal KCC2 expression and GABA function and the convergence or divergence of the pathogenic mechanisms during diabetes that induce COX-2 and GABA mediated spinal hyperalgesia will be investigated in diabetic rat models using a combination of behavioral, electrophysiological, pharmacological, biochemical and morphological techniques. The proposed studies are an extension of our recently published and preliminary data and their goal is to define the mechanisms by which diabetes alters spinal sensory processing in favor of amplified and aberrant signals so that new therapeutic targets may be identified and translated into mechanistically directed treatments that will prevent and ameliorate painful diabetic neuropathy.
Our primary aim is to investigate the mechanisms by which diabetes alters the capacity of the spinal cord to transduce sensory information passing from the periphery to the brain. The goal is to understand the role of the spinal cord in the pathogenesis of painful diabetic neuropathy so that new treatments for this debilitating condition can be developed.
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