Fructose-Induced Insulin Resistance as a Model of Neuropathic Pain in Rats.

Affiliation

Departamento de Farmacobiología, Cinvestav, Sede Sur. Mexico City, Mexico. Electronic address: [Email]

Abstract

Peripheral neuropathy is one of the main complications of diabetes. The pathogenesis of this affectation is not completely understood. Several studies refer to hyperglycemia as the principal cause of diabetic neuropathy. Nonetheless, there are changes in the expression of insulin receptor during the progress of diabetic neuropathy, suggesting that this disorder begins before high glucose blood levels are established. In this study, we investigated fructose-induced insulin resistance as a model of neuropathic pain. Insulin resistance was induced by 15% fructose in drinking water for 16 weeks. Fructose slightly enhanced blood glucose levels. In contrast, chronic fructose increased insulin plasma levels and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index. Moreover, fructose induced hyperalgesia (to 0.5% formalin) and tactile allodynia. Interestingly, gabapentin and metformin, but not diclofenac, reversed in a dose-dependent manner fructose-induced tactile allodynia. Fructose enhanced activating factor transcription 3 (ATF3), but not caspase-3 and α2δ-1 subunit, in individual L4 and L5 dorsal root ganglia (DRG) and sciatic nerve. Chronic fructose also increased anoctamin-1 and ASIC3 whereas it reduced insulin receptor-β, α5GABAA receptors and TASK-3 channels protein expression in DRG and sciatic nerve. In contrast, fructose did not change TRPV1 channel protein expression. Treatment with metformin for 4 weeks reversed some of the fructose-induced changes in protein expression. Taken together, these data suggest that insulin resistance induced by fructose reproduces several aspects of neuropathic-like pain. Our data also suggest that nociceptive hypersensitivity in this model is due to the modulation of several ionic channels at the primary afferent neurons.

Keywords

fructose,insulin resistance,metformin,neuropathic pain,tactile allodynia,

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