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Published online February 7, 2007
Diabetes 56:1569-1576, 2007
DOI: 10.2337/db06-1269
© 2007 by the American Diabetes Association
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Pathogenesis of Spinally Mediated Hyperalgesia in Diabetes

Khara M. Ramos1, Yun Jiang2, Camilla I. Svensson3, and Nigel A. Calcutt2

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

Address correspondence and reprint requests to Khara M. Ramos, Department of Pathology, University of California, San Diego, La Jolla, CA 92093-0612. E-mail: kramos{at}ucsd.edu

Abbreviations: ARI, aldose reductase inhibitor; BBB, blood-brain barrier; COX, cyclooxygenase; GFAP; glial fibrillary acidic protein; PGE2, prostaglandin E2; PNS, peripheral nervous system; STZ, streptozotocin

Hyperalgesia to noxious stimuli is accompanied by increased spinal cyclooxygenase (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 1, 2, or 4 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 pretreatment with a selective COX-2 inhibitor immediately before 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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Copyright © 2007 by the American Diabetes Association.