Pathogenesis of spinally mediated hyperalgesia in diabetes.
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.
Ramos
Khara M
KM
Department of Neurosciences, University of California, San Diego, California 92093-0612, USA. kramos@ucsd.edu
Jiang
Yun
Y
Svensson
Camilla I
CI
Calcutt
Nigel A
NA
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D006358:Hot Temperature; D006801:Humans; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology*; D007213:Indomethacin / Q000008:administration & dosage / Q000627:therapeutic use; D007278:Injections, Spinal; D007328:Insulin / Q000627:therapeutic use; D009431:Neural Conduction; D009595:Nitroparaffins / Q000494:pharmacology; D010146:Pain / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time; D012584:Sciatic Nerve / Q000503:physiopathology; D013122:Spinal Diseases / Q000201:enzymology / Q000503:physiopathology*; D013450:Sulfones / Q000494:pharmacology; D013997:Time Factors
D007328:Insulin; D009595:Nitroparaffins; D013450:Sulfones; C097934:ICI 222155; D000449:Aldehyde Reductase; D051546:Cyclooxygenase 2; D007213:Indomethacin