In the six decades that have followed the work of Hodgkin and Huxley, multiple generations of neuroscientists and biophysicists have built upon their pivotal contributions. It is now clear that, in mammals, nine genes encode nine distinct voltage-gated sodium channels with different amino acid sequences and different physiological and pharmacological properties. The different sodium channel isoforms produce a multiplicity of distinct sodium currents with different time-dependent characteristics and voltage dependencies, which interact with each other and with the currents produced by other channels (including calcium and potassium channels) to shape neuronal firing patterns. Expression of these sodium channel isoforms is highly dynamic, both in the normal nervous system, and in the injured nervous system. Recent research has shed light on the roles of sodium channels in human disease, a development that may open up new therapeutic strategies. This article examines the pain-signalling system as an example of a neuronal network where multiple sodium channel isoforms play complementary roles in electrogenesis and a strong link with human disease has been established. Recent research suggests that it may be possible to target specific sodium channel isoforms that drive hyperexcitability in pain-signalling neurons, thereby providing new therapeutic strategies for chronic pain, and providing an illustration of the impact of the Hodgkin-Huxley legacy in the clinical domain.
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