From a therapeutic point of view, cutting off pain signals within the primary afferent nociceptor might be predicted to have fewer side effects than targeting a process within the central nervous system. To validate this approach, injection of the local anaesthetic lidocaine, which blocks all NaV subunits, at painful foci in patients suffering from painful neuropathy greatly diminished allodynia, suggesting that ongoing nociceptor input drives neuropathic pain [
50]. What makes targeting of NaV subunits particularly appealing is that some neuropathic pain patients experience pain as a result of gain-of-function NaV mutations (for a review of these and other pain-related mutations, see [
11‐
13]). The NaV1.7 subunit is commonly affected, mutations often causing a shift in the activation threshold (a smaller stimulus evokes pain) and/or slow inactivation (once activated the nerve fires for longer) [
51,
52]. There are also NaV1.7 mutations that produce congenital insensitivity to pain [
53,
54], but are not associated with serious systemic side effects (likely due to NaV1.7 expression being largely restricted to the peripheral nervous system), which suggests that selective inhibition of NaV1.7 could result in pain relief without producing a plethora of neurological side effects. Transgenic mouse models where NaV1.7 has been deleted in different neuronal subsets have demonstrated its critical contribution to different forms of pain [
55], and recent work suggests that NaV1.7 activity also regulates endogenous opioid release, such that combining an NaV1.7 inhibitor with an opioid may provide synergistic analgesia with fewer side effects [
56]. A recent Phase 2a trial in trigeminal neuralgia patients demonstrated that the selective NaV1.7 inhibitor BIIB074 produced fewer treatment failures than placebo and a better improvement in the daily pain score than placebo during the double-blind phase [
57], results that are encouraging, but clearly larger trials are needed, especially those aimed at determining if BIIB074 is actually more efficacious and/or provides a lower side effect burden than the current first-line medications for trigeminal neuralgia, such as carbamazepine. Mutations in NaV1.8 can also underlie painful neuropathy in humans [
58] and transgenic mouse work has identified a critical role for NaV1.8 in acute cold pain [
59,
60], as well as cold allodynia in some neuropathic pain models [
61]. Finally, mutations in NaV1.9 can cause both congenital insensitivity to pain [
62] and painful neuropathy [
63] in humans, and transgenic mouse work supports a role for NaV1.9 in inflammatory [
64], neuropathic [
61], and visceral pain [
65], suggesting that like NaV1.7 and NaV1.8, NaV1.9 could be targeted to produce pain relief in certain neuropathic pain conditions. However, a key challenge for targeting any NaV subunit is to develop high enough subunit specificity to avoid off-target effects (e.g., inhibition of cardiac NaV1.5); a future possibility may be target modulators of NaV alpha subunits, rather than the alpha subunits themselves, for example beta subunits that modulate alpha subunit biophysical activity [
66]. By contrast with inhibiting NaV subunits, there are numerous voltage-gated potassium channels (Kv) involved in sensory neurone action potential generation, which could also be targeted by a channel opener drug to relieve neuropathic pain [
67,
68]. One promising example is retigabine, which is a Kv7 opener used as an anticonvulsant, but has also been shown to attenuate neuropathic pain in rodents [
69]. However, a recent clinical trial looking at the effects of retigabine for treating postherpetic neuralgia, failed to find any difference compared to placebo in the primary endpoint of a change from baseline in the average pain score in the last 7 days of the maintenance phase [
70].
In terms of action potential transmission, hyperpolarisation activated, cyclic nucleotide-gated ion channel (HCN) subunits are activated during the repolarization phase of action potential firing and are critical in returning a neurone to its resting membrane potential. The HCN2 subunit is predominantly expressed in sensory neurones and can be modulated by cyclic adenosine monophosphate (cAMP) to fire at more depolarised potentials, which induces trains of action potential firing [
71]. The modulation of HCN2 by cAMP may well be important, because mice lacking HCN2 in a subset of sensory neurones fail to develop neuropathic pain [
72] and ivabradine, which is a non-selective, peripherally restricted anti-anginal drug, reverses neuropathic pain in mice as effectively as gabapentin [
73]. To date, however, no clinical trials have been published on the use of ivabradine for neuropathic pain. A potential complication lies in ivabradine’s non-selectivity, such that its blockade of cardiac HCN4 produces bradycardia at similar doses to those producing a relief from neuropathic pain [
73], and thus, the search is on for a selective HCN2 inhibitor.