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 th e aldose reductase inhibitor, Tolrestat, on the pain behavior evoked b y injection of formalin into the dorsum of a single hind paw. In contr ol rats, injection of formalin (50 mu l of a 5% solution) evoked two p hases of flinching of the injected paw (phases 1 and 2), separated by a quiescent period. Four weeks of streptozotocin-induced diabetes or g alactose 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 hy perglycemia prevented the accumulation of the polyol pathway metabolit es sorbitol and fructose in the nerve and spinal cord of streptozotoci n-diabetic rats and also significantly (P < 0.05) reduced the enhanced flinching of diabetic rats during the quiescent period. These data de monstrate that hyperglycemia induces a period of Tolrestat-preventable hyperalgesia in a paradigm that is used to model persistent pain and suggest that exaggerated flux through aldose reductase may initiate ch anges in nociceptive pathways that could contribute to some of the pai n states experienced by patients with diabetic neuropathy.