The anti-diabetic drug metformin has been shown to reduce pain hypersensitivity in preclinical models of chronic pain and in neuropathic pain in humans. Multiple intracellular pathways have been described as metformin targets. Among them, metformin is an activator of the adenosine 5'-monophosphate protein kinase (AMPK) that can in turn modulate the activity of the E3 ubiquitin ligase NEDD4-2 and thus posttranslational expression of voltage gated sodium channels (Nas). In this study, we found that the bulk of the effect of metformin on Na1.7 is dependent on NEDD4-2. In HEK cells, the expression of Na1.7 at the membrane fraction, obtained by a biotinylation approach, is only reduced by metformin when co-transfected with NEDD4-2. Similarly, in voltage clamp recordings, metformin significantly reduced Na1.7 current density when co-transfected with NEDD4-2. In mouse dorsal root ganglion (DRG) neurons, without changing the biophysical properties of Na1.7, metformin significantly decreased Na1.7 current densities, but not in Nedd4L knockout mice ( ). In addition, metformin induced a significant reduction in NEDD4-2 phosphorylation at the Serine 328 residue in DRG neurons, an inhibitory phosphorylation site of NEDD4-2. In current clamp recordings, metformin reduced the number of action potentials elicited by DRG neurons from , with a partial decrease also present in mice, suggesting that metformin can also change neuronal excitability in an NEDD4-2-independent manner. We suggest that NEDD4-2 is a player for the effect of metformin on the excitability of nociceptive neurons; this action may contribute to the relief of neuropathic pain.Metformin is a multi-target, anti-diabetic drug that has shown therapeutic potential to reduce neuropathic pain. The intracellular mechanisms leading to a reduction in hyperexcitability and pain hypersensitivity remain unclear. We found that metformin acts through the activity of the E3-ubiquitin ligase NEDD4-2 to reduce cell surface expression and currents of voltage gated sodium channels (Nas), especially the Na1.7 isoform. In current clamp experiments, metformin reduced the DRG neuron firing frequency, with a smaller effect in knockout mice ( ). On the other hand, NEDD4-2 is indispensable for the metformin effect on the rheobase and the resting membrane potential of DRG neurons. These results suggest that NEDD4-2 activity is a crucial actor, although not exclusive, to reduce the excitability of nociceptive neurons.