Mini-review - Sodium Channels and Beyond in Peripheral Nerve Disease: Modulation by Cytokines and Their Effector Protein Kinases

Peripheral neuropathy is associated with enhanced activity of primary afferents which is often manifested as pain. Voltage-gated sodium channels (VGSCs) are critical for the initiation and propagation of action potentials and are thus essential for the transmission of the noxious stimuli from the periphery. Human peripheral sensory neurons express multiple VGSCs, including Nav1.7, Nav1.8, and Nav1.9 that are almost exclusively expressed in the peripheral nervous system. Distinct biophysical properties of Nav1.7, Nav1.8, and Nav1.9 underlie their differential contributions to finely tuned neuronal firing of nociceptors, and mutations in these channels have been associated with several inherited human pain disorders. Functional characterization of these mutations has provided additional insights into the role of these channels in electrogenesis in nociceptive neurons and pain sensation. Peripheral tissue damage activates an inflammatory response and triggers generation and release of inflammatory mediators, which can act through diverse signaling cascades to modulate expression and activity of ion channels including VGSCs, contributing to the development and maintenance of pathological pain conditions. In this review, we discuss signaling pathways that are activated by pro-nociceptive inflammatory mediators that regulate peripheral sodium channels, with a specific focus on direct phosphorylation of these channels by multiple protein kinases.