Voltage-gated sodium (NaV) channels are obligate components of the electrogenic machinery that underlie action potential electrogenesis (1). Nine members of the pore-forming α-subunit in the mammalian NaV channel family, expressed in a tissue-specific manner, have distinct biophysical properties and can be grouped into two pharmacologically distinct classes, as tetrodotoxin sensitive (TTX-S) and resistant (TTX-R) (2). The Nav α subunit (Figure 1A) consists of four homologous domains (DI–DIV), each with six transmembrane segments (S1–S6) that are functionally organized into a voltage-sensing module (S1–S4), and a pore module (S5 and S6 and P-loop), with cytoplasmic N- and C-termini and loops that join the four domains (L1–L3) (3). The sequences of the transmembrane segments and L3 are highly conserved, whereas the N- and C-terminus and L1 and L2 are more diverse in length and primary sequence, which suggests that these parts of the channel may contribute to differential distribution in neuronal compartments and impart distinct biophysical properties on channel isoforms.

Sodium channel structure offers multiple inhibitory modalities to treat excitability disorders including pain. (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.

Primary sensory neurons are responsible for the transduction of environmental stimuli and the transmission of the signal to the first synapse in the dorsal horn of the spinal cord, and their sensitization contributes to the induction and maintenance of chronic pain (4). Adult mammalian sensory neurons in dorsal root ganglion (DRG) and trigeminal ganglion express multiple TTX-S (NaV1.1, NaV1.6, NaV1.7) and TTX-R (NaV1.8, NaV1.9) channel isoforms (5, 6); the TTX-S NaV1.3 channel is expressed during embryonic development and reemerges following injury (7). Human and animal studies have confirmed that an increase in NaV channel levels or gain-of-function in biophysical properties lead to neuronal hyperexcitability (Figure 1B), which contributes to peripheral sensory neuron sensitization leading to pain (5, 6), supporting the idea that these channels are opportune targets for the development of therapeutic strategies for pain disorders.

While multiple nonselective NaV channel pore-blocker inhibitors, which attenuate neuronal firing (Figure 1C), are routinely used for treatment of another hyperexcitability disorder, epilepsy, fewer have been successfully used for the treatment of painful disorders such as trigeminal neuralgia, albeit with side effects that can lead to treatment withdrawal (8), and are not among those recommended for first line treatment of neuropathic pain (9). This dearth has resulted in efforts to target NaV channels that are preferentially expressed in peripheral neurons and may yield analgesics with minimal side effects. Chief among these targets has been the NaV1.7 channel because of strong genetic validation in humans; gain-of-function mutations cause painful disorders while loss-of-function mutations cause loss of pain (5, 6). However, small molecule inhibitors of NaV1.7, which bind to the voltage sensor module (VSM) and induce state-dependent inhibition of the channel, or nonselective pore blockers (Figure 1C), have not cleared clinical testing, possibly due to limited target engagement in vivo (8) and/or to autonomic symptoms from on-target effects on NaV1.7 in sympathetic and parasympathetic neurons and baroreceptors (10, 11). It is notable that subjects with Nav1.7-related congenital insensitivity to pain and those on long-term treatment with pan sodium channel blockers do not report these autonomic deficits (12), which suggests that development of safer Nav1.7 blockers might be possible, as the basis of the sparing of autonomic function in these subjects becomes better understood. Recently, a selective small molecule blocker of NaV1.8, VX-548, has been shown to produce partial pain relief in Phase 3 clinical trials of acute pain (13, 14). A CNS-penetrant aryl sulfonamide small molecule NaV1.6 selective blocker (15) is in a Phase 2 clinical trial as an adjunctive therapy for seizures produced by mutations of SCN8A (the gene encoding Nav1.6), but has not yet been tested in pain conditions; on-target side effects will have to be monitored closely because of the channel’s widespread expression in the CNS and PNS neurons. It remains to be seen whether small molecules can achieve sufficient inhibition of single NaV channel isoforms to provide effective monotherapies for chronic pain or whether multi-channel blockade is required for effective analgesia.