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Pathogenesis of spinally mediated hyperalgesia in diabetes

¹Department of Neurosciences, University of California, San Diego, CA, USA
²Department of Pathology, University of California, San Diego, CA, USA
³Department of Anesthesiology, University of California, San Diego, CA, USA

Correspondence: kramos{at}ucsd.edu

Hyperalgesia to noxious stimuli is accompanied by increased spinal cyclooxygenase-2 (COX-2) protein in diabetic rats. The present studies were initiated to establish causality between increased spinal COX-2 activity and hyperalgesia during diabetes, and to assess the potential involvement of polyol pathway activity in the pathogenesis of spinally-mediated hyperalgesia. Rats with one, two or four weeks of streptozotocin-induced diabetes exhibited significantly increased levels of spinal COX-2 protein and activity, along with exaggerated paw flinching in response to 0.5% paw formalin injection. Increased flinching of diabetic rats was attenuated by intrathecal pre-treatment with a selective COX-2 inhibitor immediately prior to formalin injection, confirming the involvement of COX-2 activity in diabetic hyperalgesia. Chronic treatment with insulin or ICI222155, an aldose reductase inhibitor (ARI) previously shown to prevent spinal polyol accumulation and formalin-evoked hyperalgesia in diabetic rats, prevented elevated spinal COX-2 protein and activity in diabetic rats. In contrast, the ARI IDD676 had no effect on spinal polyol accumulation, elevated spinal COX-2, or hyperalgesia to paw formalin injection. In the spinal cord, aldose reductase immunoreactivity was present solely in oligodendrocytes, which also contained COX-2 immunoreactivity. Polyol pathway flux in spinal oligodendrocytes provides a pathogenic mechanism linking hyperglycemia to hyperalgesia in diabetic rats.

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