Physiological Role of Slow Sodium Channels in Primary Sensory Coding of Nociceptive Information

Abstract

The Nav1.8 sodium channels of nociceptors are involved in encoding the signals generated by multimodal nociceptors, and only a high-frequency component of this impulse response alerts the brain to tissue damage and provides information about the location and type of pain. Specific reduction of the Nav1.8 functional activity should switch off the high-frequency component, thus ensuring the normal functions of multimodal mechanoreceptors, thermoreceptors, and chemoreceptors in chronic pain. Analgesics that are completely safe upon long-term administration are unavailable for treating chronic pain in medicine. Mathematical modeling based on the Hodgkin–Huxley ionic theory was performed to understand the mechanism whereby the functional activity of the Nav1.8 channel is modulated specifically and the role that the mechanism plays in primary sensory encoding of nociceptive information. The gist of the mechanism is reducing the potential sensitivity of the Nav1.8 channel by decreasing the effective charge transferred by its activation gating structure. This was shown for the first time to completely restore the normal stimulus–response function of the nociceptive neuron. Only the high-frequency component is specifically eliminated from its membrane response. The same effect can be achieved by reducing the density of slow sodium channels. However, the effect of potential pharmacological analgesics will apparently be less specific in the latter case because of their possible interactions with other members the sodium channel superfamily.