Influence of the State of TTX-Resistant Sodium Channels on Electrical Activity of a Nociceptive Sensory Fiber: A Model Study

Abstract

On a model of a thin (C-type) primary afferent fiber, we examined one of the hypotheses related to the phenomenon of initiation of long-lasting tonic discharges in nociceptive afferents. In the membrane of a region corresponding to the free peripheral terminal of the modeled nociceptive C fiber, there were sodium channels of three types (channels of rapidly inactivating TTX-sensitive current and TTX-resistant channels of two types, NaV1.8/SNS/PN3 and NaV1.9/NaN/SNS2). As is known, TTX-resistant sodium currents promote the development of long-lasting trains of action potentials, APs, where the duration of tonic discharges exceeds by orders of magnitude the duration of short stimuli inducing such discharges. Such trains, when transmitted to the spinal cord, are interpreted as pain signals. Using the model, we obtained the time course of changes in the membrane potential in the distal and proximal segments of the nerve fiber and values of the densities of inward and outward TTX-resistant sodium currents through channels NaV1.9/NaN/SNS2 and NaV1.8/SNS/PN3 in the norm and in a state mimicking the action of inflammation factors. Results of modeling demonstrated that TTX-resistant sodium currents provide intensification of slow components in the generated APs (plateau afterdepolarization). Having a higher inactivation threshold, these currents are inactivated more slowly and recover more rapidly after inactivation, as compared with the currents through TTX-sensitive sodium channels. Such behavior presupposes a considerable role of the TTX-resistant currents in facilitation of transmission of nociceptive signals under conditions of neuropathic pain characterized by excessive “upregulation” of the respective channels. It can be concluded that expression of TTX-resistant sodium channels in nociceptive sensory neurons possessing primary afferent C fibers, the presence of these channels in the membranes of peripheral terminals of the above fibers, and modification of biophysical properties of such channels under conditions of action of inflammation mediators, when taken together, create substantial prerequisites for initiation of anomalous long-lasting AP trains in the above peripheral terminals and, therefore, for transmission of such signals to the CNS. Such a situation appears to be a key electrophysiological phenomenon responsible for generation of neuropathic and inflammation-related pain.