Physiological role of slow sodium channels in primary sensory coding

Abstract

Nav1.8 sodium channels of nociceptors participate in encoding signals generated by polymodal nociceptors and only the 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 functional activity of these channels should help in “switching off” this high-frequency component, hence, the possibility of retaining the normal functioning of polymodal mechanoreceptors, thermoreceptors, and chemoreceptors in case of chronic pain. From general medical practice, it is known that in the treatment of pain, there are no safe analgesics, the use of which as a long-term therapy would be completely safe. Mathematical modeling based on the Hodkgin and Nuxley formulation describing the flow of ionic currents was used to understand the mechanism of specific modulation of the functional activity of Nav1.8 channels and its role in primary sensory encoding of nociceptive information. This mechanism is based on a reduction in the potential sensitivity of these channels due to a decrease in the effective charge transferred by their activation gating structure. It is shown for the first time that this leads to a complete restoration of the normal function of the stimulus-response of the nociceptive neuron. At the same time, only the high-frequency component of its membrane response is specifically eliminated. The same effect can be achieved by reducing the density of slow sodium channels. However, it is obvious that in the second case, the action of pharmacological substances which are supposed to be called analgesics will be less specific since the interaction with other representatives of the superfamily of sodium channels might turn out to be feasible.