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Painful diabetic neuropathy (PDN) is one of most common complication of diabetes, usually affecting 50% of diabetic patients and remains important cause of morbidity, mortality and deterioration of quality of life. PDN is well characterised by chronic hyperglycemia, alterations in expression and kinetics of voltage-gated sodium channels (VGSCs) and neuro-inflammation which together may result into sensorimotor deficits in peripheral nervous system. Peripheral nociceptive neurons express variety of sodium channel isoforms particularly Nav1.3, Nav1.7, Nav1.8 and Nav1.9, each play a key role in physiology of nociception by undergoing respective dynamic changes in expression and voltage-dependent gating properties. Thus, they are critical determinants of sensory neuronal excitability and associated neuropathic pain signal. Recent preclinical and clinical trial research has shed light on VGSCs as most compelling target in the treatment of PDN, a development that may open up new therapeutic approaches involving subtype selective sodium channel blockers to boost clinical efficacy, cost effectiveness, better tolerability and targeted treatment. In this review, we have summarized structure and functions of VGSCs and their involvement in the pathophysiology of neuropathic pain along with the current status of pharmacological interventions targeted at VGSCs in the treatment of diabetic neuropathy.

Rufinamide is a structurally novel, antiepileptic drug approved for the treatment of Lennox-Gastaut syndrome. Its mechanism of action involves inhibition of voltage-gated Na+ channels (VGSCs) with possible membrane-stabilizing effects. VGSCs play a significant role in the pathogenesis of neuropathic pain. Therefore, we investigated the effects of rufinamide on tetrodotoxin-resistant sodium current (TTX-R I(Na)) in acutely dissociated rat dorsal root ganglion (DRG) neurons isolated from streptozotocin-induced diabetic rats by using whole-cell voltage-clamp configuration. In addition, the functional and behavioural nociceptive parameters were evaluated to assess its potential in diabetic neuropathy. Diabetic rats demonstrated the mechanical allodynia and thermal hyperalgesia with reduced nerve perfusion and conduction velocity as compared to control. Rufinamide treatments (3 and 10 mg/kg) significantly improved these functional and nociceptive deficits. Diabetic rat DRG neurons exhibited increased TTX-R I(Na) density as compared to control. The voltage-dependent activation and steady-state inactivation curves for TTX-R I(Na) in DRG neurons from diabetic rats were shifted negatively as compared to control. Rufinamide treatments significantly blocked the TTX-R Na+ channel activity as evident from significant reduction in I(Na) density and hyperpolarizing shift in activation and inactivation curves as compared to diabetic control. This suggests that rufinamide acts on TTX-R Na+ channels, reduces channel activity and attenuates nerve functional and behavioral parameters in diabetic rats. Altogether, these results indicate therapeutic potential of rufinamide in the treatment of diabetic neuropathy.

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