Tolrestat treatment prevents modification of the formalin test model of prolonged pain in hyperglycemic rats.
This study examined the effects of hyperglycemia and treatment with the aldose reductase inhibitor, Tolrestat, on the pain behavior evoked by injection of formalin into the dorsum of a single hind paw. In control rats, injection of formalin (50 microliters of a 5% solution) evoked two phases of flinching of the injected paw (phases 1 and 2), separated by a quiescent period. Four weeks of streptozotocin-induced diabetes or galactose intoxication did not alter the frequency of flinching during either of the active phases but significantly (P < 0.001 and P < 0.05, respectively) enhanced flinch frequency during the quiescent period. Concurrent treatment with Tolrestat (50 mg/kg/day by gavage) during hyperglycemia prevented the accumulation of the polyol pathway metabolites sorbitol and fructose in the nerve and spinal cord of streptozotocin-diabetic rats and also significantly (P < 0.05) reduced the enhanced flinching of diabetic rats during the quiescent period. These data demonstrate that hyperglycemia induces a period of Tolrestate-preventable hyperalgesia in a paradigm that is used to model persistent pain and suggest that exaggerated flux through aldose reductase may initiate changes in nociceptive pathways that could contribute to some of the pain states experienced by patients with diabetic neuropathy.
Department of Pathology, University of California San Diego, La Jolla, CA 92093 USA Department of Anesthesiology, University of California San Diego, La Jolla, CA 92093 USA Department of Clinical Pharmacology, Sahlgrenska Hospital, GothenburgSweden.
Nigel A
NA
Calcutt
Annika B
AB
Malmberg
Tatsuo
T
Yamamoto
Tony L
TL
Yaksh
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D005260:Female; D005557:Formaldehyde; D005690:Galactose / Q000494:pharmacology; D006930:Hyperalgesia / Q000517:prevention & control; D006943:Hyperglycemia / Q000503:physiopathology*; D009281:Naphthalenes / Q000627:therapeutic use*; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control*; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D013012:Sorbitol / Q000378:metabolism
D009281:Naphthalenes; C040550:tolrestat; D005557:Formaldehyde; D013012:Sorbitol; D000449:Aldehyde Reductase; D005690:Galactose