Pathogenesis of Spinally Mediated Hyperalgesia in Diabetes
- 1Department of Neurosciences, University of California, San Diego, California
- 2Department of Pathology, University of California, San Diego, California
- 3Department 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
Abstract
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.
- ARI, aldose reductase inhibitor
- BBB, blood-brain barrier
- COX, cyclooxygenase
- GFAP
- glial fibrillary acidic protein
- PGE2, prostaglandin E2
- PNS, peripheral nervous system
- STZ, streptozotocin
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 6 April 2007. DOI: 10.2337/db06-1269.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted January 27, 2007.
- Received September 8, 2006.
- DIABETES
