Mechanical hyperalgesia in rat models of systemic and local hyperglycemia.
Mechanical hyperalgesia is an early symptom of diabetic neuropathy. To evaluate the mechanisms underlying this symptom, it was studied and compared in rat models of systemic and local hyperglycemia. Systemic hyperglycemia was induced by a single injection of streptozotocin (STZ, 50 mg/kg). Local hyperglycemia either in L(5) dorsal root ganglion (DRG) or a segment of the sciatic nerve at mid-thigh level was maintained by perfusion with 30-mM glucose solution delivered from a surgically implanted osmotic minipump. Mechanical hyperalgesia was assessed using modified von Frey filaments and hind limb withdrawal threshold measurements. During 2 weeks of STZ-induced diabetes rat systemic blood glucose level increased from 5.1+/-0.3 to 23+/-1.9 mM and limb withdrawal threshold decreased by approximately 30% bilaterally. During 2 weeks of local perfusion systemic blood glucose did not change; however, rats that underwent perfusion of the DRG or sciatic nerve with glucose exhibited a rapid (completed in approximately 1 week) 40-50% decrease in ipsilateral limb withdrawal threshold. Perfusion of the sciatic nerve with the normoglycemic buffer solution did not affect withdrawal thresholds. The aldose reductase inhibitor sorbinil (2.5 mg/ml) when added to 30-mM glucose perfusion solution prevented hyperalgesia. These data suggest that mechanical hyperalgesia in diabetic animals may, at least in part, result from focal injury caused by a direct toxic effect of glucose in the peripheral nervous system. These data also support the idea of activation of aldose reductase and polyol pathway as an important mechanism of hyperglycemia-induced impairment of nerve function.
Dobretsov
Maxim
M
Department of Anesthesiology, Slot 515, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205-7101, USA. dobretsovmaxim@uams.edu
Hastings
Stephanie L
SL
Romanovsky
Dmitry
D
Stimers
Joseph R
JR
Zhang
Jun-Ming
JM
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000473:pathology; D003929:Diabetic Neuropathies / Q000473:pathology; D004343:Drug Implants; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000473:pathology; D006930:Hyperalgesia / Q000473:pathology*; D006943:Hyperglycemia / Q000473:pathology*; D008297:Male; D010147:Pain Measurement / Q000187:drug effects; D010477:Perfusion; D017933:Peripheral Nervous System / Q000473:pathology; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000473:pathology
D001786:Blood Glucose; D004343:Drug Implants; D004791:Enzyme Inhibitors; D000449:Aldehyde Reductase