Sensory neuron voltage-gated sodium channels as analgesic drug targets

Voltage-gated sodium channels are crucial determinants of neuronal excitability and signalling; some specific channel subtypes have been implicated in a number of chronic pain conditions. Human genetic studies show gain-of-function or loss-of-function mutations in NaV1.7 lead to an enhancement or lack of pain, respectively, whilst transgenic mouse and knockdown studies have implicated NaV1.3, NaV1.8 and NaV1.9 in peripheral pain pathways. The development of subtype-specific sodium channel blockers, though clearly desirable, has been technically challenging. Recent advances exploiting both natural products and small molecule selective channel blockers have demonstrated that this approach to pain control is feasible. These observations provide a rationale for the development of new analgesics without the side effect profile of broad spectrum sodium channel blockers.