(A) The pore-forming α-subunit of sodium channels has 24 transmembrane segments, organized into four domains (I, II, III, and IV), linked by three cytoplasmic loops (L1–3), with a cytoplasmic N- and C-termini of the polypeptide. The cytoplasmic regions of the TTX-S channels carry SLiMs, including sites for posttranslational modifications, e.g. p38 MAPK phosphorylation (PXSP), binding channel partners that regulate channel trafficking and reduce number of channels at the cell surface (CRMP2 Regulatory Sequence, CRS; PXY, which binds NEDD4 family of E3 ubiquitin ligases), and binding of NaviPA1, which reduces current density of multiple TTX-S channels, albeit via an unknown mechanism. (B) TTX-S Nav channels contribute to hyperexcitability of sensory neurons as reflected by repetitive action potential firing. (C) There are multiple strategies for targeting Nav channels, including those mediated by SLiMs, (e.g., via CRMP2, NEDD4, and NaviPA1). Other strategies include small molecule inhibitors that reduce the amplitude of the Nav current by blocking the channel pore (e.g., TTX and its derivatives), while others also stabilize inactivated states of the channel (e.g., local anesthetics). Peptide toxins can also act as pore blockers, and others bind to the VSM and modulate gating properties. Biologics like antibodies and nanobodies that target channels at the cell surface provide another possible approach, albeit without reportable success to date. Inhibition of Nav channels by these different modalities attenuates firing of sensitized neurons leading to analgesia.