Diabetes is one of the leading causes of
painful neuropathy and to date, besides a tight
glycemic control, a viable treatment for this complication is not available.
Rimonabant is a selective
cannabinoid CB(1) receptor antagonist that produces a significant increase in
insulin sensitivity and a reduction of HbA(1c) in diabetic patients. This study aimed to investigate the therapeutic potential of
rimonabant in relieving diabetes-induced
neuropathic pain. The repeated treatment with
rimonabant evoked a significant attenuation of
mechanical allodynia in diabetic mice that was dose- and time-dependent. This effect occurred without alteration of
hyperglycemia, but it was associated with significant effects on many key players in the pathogenesis of
diabetic neuropathy. Metabolic changes induced by
hyperglycemia lead to oxidative stress, deregulation of
cytokine control and reduced production and transport of
nerve growth factor (
NGF), and all these factors contribute to
neuropathic pain.
Rimonabant treatment reduced oxidative stress in peripheral nerve, as revealed by the ability of the compound to counteract the
reduced glutathione (GSH) depletion. The same repeated treatment inhibited
tumor necrosis factor (
TNFalpha) overproduction in the spinal cord and increased the
NGF support. This
rimonabant-induced improvement might favour the nerve regeneration; accordingly, the histological analysis of sciatic nerves showed a marked degeneration of myelinated fibers in diabetic mice, that was substantially reduced after
rimonabant administration. These findings support the hypothesis that CB(1) antagonists would represent a new opportunity for diabetic patients, since currently there are no treatments for
painful diabetic neuropathy other than treating the diabetic condition per se.