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Voltage-gated sodium channels (NaV) are the main contributors to action potential generation and essential players in establishing neuronal excitability. NaV channels have been widely studied in pain pathologies, including those that develop during diabetes. Diabetic sensory neuropathy (DSN) is one of the most common complications of the disease. DSN is the result of sensory nerve damage by the hyperglycemic state, resulting in a number of debilitating symptoms that have a significant negative impact in the quality of life of diabetic patients. Among those symptoms are tingling and numbness of hands and feet, as well as exacerbated pain responses to noxious and non-noxious stimuli. DSN is also a major contributor to the development of diabetic foot, which may lead to lower limb amputations in long-term diabetic patients. Unfortunately, current treatments fail to reverse or successfully manage DSN. In the current review we provide an updated report on NaV channels including structure/function and contribution to DSN. Furthermore, we summarize current research on the therapeutic potential of targeting NaV channels in pain pathologies, including DSN.

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes. It is characterized by a constellation of sensory abnormalities, including numbness, tingling, burning, and painful sharp, shooting sensations in the extremities. Patients with DPN are also at high risk for infection and amputation. Traditionally, neuropathy has been considered to result from peripheral nerve damage after long term diabetes, however more recent indicate that functional changes take place in early stages of diabetes. One of those changes is the increased expression and signalling of the receptor for advance glycation end-product (RAGE), which is known to have a pivotal role in the development of diabetic complications. In the current study we concentrate on T-type (Cav 3.2) channels, which are low voltage-activated calcium channels that play a key role in cellular excitability, and have been reported to contribute to pain abnormalities in rat models of DPN. The goal of this project is to elucidate the role of Cav 3.2 during early stages of diabetes in sensory neurons from the dorsal root ganglion (DRG) of mice, and its possible regulation through the RAGE pathway. We used cultured DRG neurons from wilt-type (WT) and RAGE knock-out (RAGE KO) mice maintained in control (5mM) or high glucose (25 mM) for up to 14 days, as well as intact DRG ganglia from streptozotocin (STZ)-induced diabetic mice (WT and RAGE KO) for 4 weeks. Using whole cell patch-clamp electrophysiology and protein biochemistry we revealed changes in the activation kinetics and expression levels of Cav 3.2 channels. Our data suggest that RAGE-dependent changes in Cav 3.2 expression and function may contribute to functional abnormalities in sensory neurons during early hyperglycemia. Disclosure J.T. Neapetung: None. V.A. Campanucci: None.

Peripheral neuropathy in diabetes is characterized by a constellation of sensory abnormalities, including numbness, tingling, as well as exacerbated responses to painful and non-painful stimuli. Particular interest has concentrated on voltage-gated sodium (Nav) channels since they play central roles in painful forms of neuropathy in long-term diabetes. However, their possible contributions to the onset of neuropathy are still under investigation. In the current study, we aimed at elucidating the contribution of Nav channels during early hyperglycemia in sensory neurons from the Dorsal Root Ganglion (DRG). We used cultured DRG neurons, maintained in either control (5 mM glucose) or in high glucose media (25 mM) for up to 14 days, and intact DRG tissues from streptozotocin (STZ)-induced hyperglycemic mice (at 1 and 3 months after induction). To study Nav channel function we used whole-cell patch-clamp electrophysiology and biochemical analysis by Western blotting for the detection of Nav subunit expression. Our results indicate that DRG neurons maintained in high glucose showed reduced action potential firing frequency and reduced inward currents. The later was consistent with the downregulation of the tetrodotoxin sensitive (TTX-S) Nav1.3, Nav1.6, and Nav1.7 subunits in intact DRG tissues from one-month STZ-hyperglycemic mice. The Navβ2 subunit, which has been shown to regulate the cell surface expressions of TTX-S Nav channels, also shows reduced expression levels. Interestingly, after three months of STZ-induced hyperglycemia, there was a significant upregulation in the expression level of the TTX-S Nav1.7 subunit, which has been linked to painful forms of neuropathy. Taken together, our data revealed that changes in expression and function of TTX-S Nav subunits take place from the early stage of pathologic hyperglycemia. Therefore, our data suggest that Nav channel may be involved in the development of positive and negative sensory symptoms in diabetic neuropathy. Disclosure V.A. Campanucci: None. M. Bautista: None. J.T. Neapetung: None. Funding Natural Sciences and Engineering Research Council of Canada (RGPIN-2015-03958)