Na_v1.7 has seen special interest in recent years as several inherited human pain disorders, including congenital pain insensitivity, have been shown to result from mutations in this channel (see Sect. 3). The Na_v1.7 channel is characterised biophysically as a tetrodotoxin-sensitive, fast-activating and a fast-inactivating channel that recovers slowly from fast inactivation (Klugbauer et al. 1995). Na_v1.7 also has slow closed-state inactivation properties, allowing the channel to generate a ramp current in response to small, slow depolarisations (Cummins et al. 1998; Herzog et al. 2003). Na_v1.7-positive neurons are therefore able to amplify slowly developing subthreshold depolarising inputs, such as generator potentials arising in peripheral terminals of nociceptors. Na_v1.7 is expressed within DRG and trigeminal ganglia peripheral sensory neurons, as well as sympathetic neurons and olfactory epithelia (Toledo-Aral et al. 1997; Weiss et al. 2011). Na_v1.7 shows particularly high expression within the soma of small-diameter DRG neurons and along the peripherally and centrally directed C fibres of these cells (Black et al. 2012). Expression can also be detected within the peripheral terminals of DRG neurons in the skin and also in the preterminal central branches and terminals in the dorsal horn, as well as at nodes of Ranvier in a subpopulation of small-diameter myelinated fibres.

In 2004, conditional deletion of Na_v1.7 within Na_v1.8-positive nociceptors highlighted the importance of this channel to pain behaviour, with knockout animals losing acute noxious mechanosensation and inflammatory pain (Nassar et al. 2004). In 2012, an Advillin Cre line was used to ablate Na_v1.7 expression in all DRG sensory neurons, with knockout mice showing an additional loss of noxious thermosensation (Minett et al. 2012). This suggests that Na_v1.7 expressed within Na_v1.8-positive sensory neurons is important for acute noxious mechanosensation, whilst Na_v1.7 expressed within Na_v1.8-negative DRG neurons is essential for acute noxious thermosensation. The contribution of Na_v1.7 to the development of neuropathic pain behaviour has also been assessed using different Cre mice to delete Na_v1.7 in subgroups of cell populations. Neuropathic pain behaviour develops normally in mice where Na_v1.7 has been deleted in Na_v1.8-positive sensory neurons and in Advillin-positive DRG neurons (Nassar et al. 2005; Minett et al. 2012). In contrast, mice in which Na_v1.7 is deleted from all sensory neurons as well as sympathetic neurons (using a Wnt1-Cre) show a dramatic reduction in mechanical hypersensitivity following a surgical model of neuropathic pain, demonstrating an important role for Na_v1.7 in sympathetic neurons in the development of neuropathic pain (Minett et al. 2012).

The TTX-resistant Na_v1.8 sodium channel is expressed in the majority of small-diameter unmyelinated nociceptive DRG neurons (Akopian et al. 1996). Na_v1.8 displays ~10-fold slower kinetics with a depolarised voltage dependence of activation and inactivation than the fast and rapidly inactivating TTX-S DRG channels (Akopian et al. 1996; Cummins and Waxman 1997). Analysis of Na_v1.8 null mice shows that Na_v1.8 carries the majority of the current underlying the upstroke of the action potential in nociceptive neurons (Akopian et al. 1999; Renganathan et al. 2001). Furthermore, Na_v1.8 is cold resistant, meaning that it is essential in maintaining the excitability of nociceptors at low temperatures (Zimmermann et al. 2007).

In contrast to Na_v1.7 global knockout mice, Na_v1.8 null mice are viable, fertile and apparently normal (Akopian et al. 1999). However, pain behaviour analyses show that Na_v1.8 null mice have reduced sensitivity to noxious mechanical stimuli (tail pressure), noxious thermal stimuli (radiant heat) and are insensitive to noxious cold stimuli (Akopian et al. 1999; Zimmermann et al. 2007) (Table 2). Furthermore, Na_v1.8 is important in nerve growth factor-induced thermal hyperalgesia, although neuropathic pain behaviour is normal in these mice following peripheral nerve injury (Kerr et al. 2001). Transgenic mice in which Na_v1.8-expressing neurons are ablated by the targeted expression of diphtheria toxin A are resistant to noxious cold and noxious mechanical stimuli but show a normal hot plate response (Abrahamsen et al. 2008). Furthermore, mechanical and thermal hyperalgesia induced by inflammatory insults is attenuated in these mice, although neuropathic pain behaviour is normal.

Na_v1.9 was cloned in 1998 and has a similar expression pattern within DRG to Na_v1.8 (Dib-Hajj et al. 1998; Fang et al. 2002). Na_v1.9 generates extremely slow persistent TTX-resistant currents and can be activated at potentials close to the resting membrane potential (Cummins et al. 1999; Dib-Hajj et al. 2002). The activation kinetics are too slow to contribute to the upstroke of an action potential, although Na_v1.9 may amplify subthreshold depolarisations and lower the threshold for action potential induction (Cummins et al. 1999; Herzog et al. 2001; Baker et al. 2003). Mice lacking the Na_v1.9 channel have normal sensitivity to acute mechanical and thermal noxious stimuli suggesting that Na_v1.9 is not essential for setting basal pain thresholds; however, under inflammatory conditions, the channel plays a predominant role in mechanical and thermal hyperalgesia (Table 2) (Priest et al. 2005; Amaya et al. 2006; Lolignier et al. 2011).

Na_v1.3, like Na_v1.7, is a TTX-sensitive channel with fast kinetics and a rapid recovery from fast inactivation. Unlike Na_v1.7, Na_v1.3 has very low expression levels in the DRG in adults, instead having a predominant expression pattern in the central and peripheral nervous system during embryogenesis (Beckh et al. 1989; Waxman et al. 1994). In humans, Na_v1.3 is widely expressed in adult brain and is thought to play a role in propagating synaptic signals from dendrites to the soma and integration of electrical signals within the soma prior to the initiation of axonal action potentials (Whitaker et al. 2001). Na_v1.3 levels increase in peripheral sensory neurons following nerve injury or inflammation, suggesting that this channel could play a role in pain (Waxman et al. 1994; Dib-Hajj et al. 1999). However, Na_v1.3 global and nociceptor-specific knockout mice show normal neuropathic pain behaviour (Table 2) (Nassar et al. 2006).