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Exp Neurol. Author manuscript; available in PMC Mar 1, 2009.
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PMCID: PMC2312090
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Na+ channel blockers for the treatment of pain: context is everything, almost

Voltage-gated Na+ channels (VGSCs) remain viable targets for the development of novel analgesics for two main reasons. First, because of they underlie the upstroke of the action potential, a block of these channels results in a block of neural activity and therefore a block of pain. Second, functional diversity and selective expression patterns of channel types indicate that it may be possible to selectively block persistent pain associated with peripheral tissue injury. Importantly, this block may be possible with little impact on acute pain or low threshold mechanosensation, and no cardiac or central nervous system side effects.

A single alpha subunit is necessary and sufficient to generate a functional VGSC. The VGSC alpha subunit is a large molecule (>200 kd) encompassing 4 domains (I–IV) with similar structures that consist of 6 transmembrane segments (S1–S6) (Catterall, et al., 2005). The fourth segment in each domain contains the voltage sensor. A loop between S5 and S6 lines the channel pore and confers ion selectivity. A unique hydrophobic sequence, the IMF motif, in the intracellular loop between domains III and IV has access to and can block the inner mouth of the pore when the channel is open. The IMF mediated block of open channels mediates channel inactivation. Nine alpha subunits (NaV1.1 – NaV1.9) have been characterized. A tenth alpha subunit (NaX) has been identified, but it does not appear to function as a voltage-gated channel (Catterall, et al., 2005).

Unique features of each of the alpha subunits are largely responsible for unique biophysical properties of the channel (i.e., the voltage range over which the channel begins to open, the voltage-dependence and rate of inactivation, the rate of recovery from inactivation) and therefore channel function. However, the alpha subunits do associate with beta subunits, 4 of which have been identified, that may also influence the channel properties, density and distribution within a cell (Isom, 2000, Yu, et al., 2003). Several other molecules have been identified that appear to play in important role in VGSC trafficking to the cell membrane including Annexin II/p11, contactin, and clathrin-associated protein-1A (CAP-1A). Annexin II/p11 is involved in trafficking NaV1.8 channels to the cell membrane (Okuse, et al., 2002). Contactin, associates directly with, and regulates the density of, NaV1.3 (Shah, et al., 2004) and NaV1.9 (Liu, et al., 2001); although data from a contactin null mutant mouse suggests the role of this protein may be more complicated as the knockout resulted in a reduction in both NaV1.8 and NaV1.9 in primary afferent cell body and axons, but no change in TTX-sensitive current or channels (Rush, et al., 2005). CAP-1A serves to link NaV1.8 to clathrin and appears to contribute to the clathrin mediated removal of this channel from the cell membrane (Liu, et al., 2005).

The density and distribution of channels both within and between tissues may be a particularly important determinant of channel function (Lai, et al., 2004). For example, NaV1.4 and NaV1.5 are largely restricted, in the adult, to skeletal and cardiac myocytes and are therefore, responsible for the excitability of these tissues. Similarly, NaV1.1 and NaV1.3 are primarily localized to the soma of neurons in the central nervous system where they function to integrate synaptic activity, while NaV1.6 is localized in nodes of Ranvier in myelinated axons in both the central and peripheral nervous system where it underlies action potential propagation. Finally, alpha subunits also contain a number of phosphorylation sites, particularly in the intracellular linker between domains I and II that enable dynamic regulation of channel properties (Chen, et al., 2006): depending on the subunit, channels have been shown to be up or down regulated by second messenger pathways involving the activation of protein kinase A (Cantrell and Catterall, 2001, Fitzgerald, et al., 1999, Gold, et al., 1998), protein kinase C (Cantrell and Catterall, 2001, Gold, et al., 1998), sphingomyelinase (Zhang, et al., 2002), calmodulin (Herzog, et al., 2003), and p38 MAP kinase (Jin and Gereau, 2006, Wittmack, et al., 2005).

If the selective distribution and essential role in action potential generation were not enough motivation for the development of selective VGSC blockers for the treatment of pain, there is evidence that several VGSC alpha subunits may be responsible for pain associated with tissue injury. The first channel to be implicated was NaV1.3 which is normally only present in the peripheral nervous system during embryogenesis. However, there is a dramatic increase in the expression of this alpha subunit following peripheral nerve injury (Waxman, et al., 1994). A unique feature of this channel is that it recovers relatively rapidly from inactivation (Cummins, et al., 2001). Thus, the increase in expression combined with unique biophysical properties led to the natural hypothesis that this channel contributes to paraesthesias, dysaesthesias and ongoing pain that are hallmarks of peripheral neuropathy. Consistent with this hypothesis, there is evidence that selectively knocking down expression of this channel with antisense oligodeoxynucleotides attenuates peripheral nerve injury-induced mechanical hypersensitivity (Hains, et al., 2004). More recent data (Lindia, et al., 2005, Nassar, et al., 2006), however, has led investigators to question the role of this channel in neuropathic pain.

A second VGSC directly linked to pain associated with tissue injury is NaV1.7. Compelling evidence in support of a causal link between this channel and pain comes from the discovery of individuals harboring both gain-of-function and loss-of-function mutations in the channel. Two different gain-of-function mutations are associated with two distinct pain syndromes. One of these, erythermalgia is a rare disorder associated with pain and redness in the feet and hands (Yang, et al., 2004). Several different NaV1.7 mutations have been identified in patients with erythermalgia, all of which appear to be associated with an increase in channel function (Waxman and Dib-Hajj, 2005). Interestingly, at least one of the mutations results in a depolarization of resting membrane potential which both increases the excitability of primary afferent neurons and decreases the excitability of sympathetic postganglionic neurons (Rush, et al., 2006); it is the combination of these two changes that is likely to account for the striking symptoms of this disorder. The second gain-of-function mutation in NaV1.7 is associated with paroxysmal pain disorder (Fertleman, et al., 2006). This mutation results in a decrease in the rate and/or extent of channel inactivation. The result is a Na+ current that persists following repolarization of the action potential which serves as the driving force for subsequent action potential generation. As with erythermalgia, paroxysmal pain disorder impacts specific body regions, most commonly the anal sphincter, despite the fact that the mutant channels are expressed throughout the peripheral nervous system. This observation serves as a reminder that despite their importance in controlling neuronal excitability, VGSC do not function in isolation as other mechanisms appear able to mitigate the impact of the channelopathy in unaffected tissue. That said, the loss of function mutation of NaV1.7 results in what appears to be complete insensitivity to pain (Cox, et al., 2006). Interestingly, individuals harboring this mutation exhibit few, if any, detectable somatosensory abnormalities.

Analysis of the cohort with a loss of function mutation in NaV1.7 supports a role for this channel in acute nociceptive processing and several additional lines of evidence support a role for this channel in inflammatory hyperalgesia: NaV1.7 mRNA (Black, et al., 2004) and protein (Black, et al., 2004, Gould, et al., 2004) are increased in the presence of inflammation in association with an increase in TTX-sensitive current (Black, et al., 2004); inflammatory hyperalgesia is attenuated following knock-down of the channel in rats (Yeomans, et al., 2005); and inflammatory hypersensitivity is either absent or dramatically attenuated in mice in which the channel was selectively knocked out in nociceptive afferents (Nassar, et al., 2004). Evidence against a role for NaV1.7 in neuropathic pain was suggested by the observations that in patients with peripheral nerve injury NaV1.7 protein appears to decrease in the DRG neurons and remains undetectable in injured peripheral nerve (Coward, et al., 2001) and that there appears to be no deficit in the nerve injury-induced hypersensitivity in nociceptors specific NaV1.7 null mutant mice (Nassar, et al., 2004). More recently, however, an NaV1.7 selective blocker was described (Hoyt, et al., 2007) that is said to reverse hypersensitivity in animal models of nerve injury (Hoyt, et al., 2007).

A third VGSC that appears to play a critical role in pain associated with tissue injury is NaV1.8, the focus of the study by Yamane and colleagues in this issue (Yamane, et al., 2007). What makes NaV1.8 a particularly attractive target for the development of a selective channel blocker is that it is only expressed in sensory neurons (Akopian, et al., 1996, Sangameswaran, et al., 1996) and among these, it is largely restricted to nociceptive neurons (Djouhri, et al., 2003). Furthermore, within nociceptive neurons, it appears to be primarily targeted to terminals and the cell body, suggesting a role in action potential initiation (Lai, et al., 2004). The biophysical properties of the channel are also consistent with a role in mediating sustained activity in the presence of persistent membrane depolarization as would be expected in the presence of inflammatory mediators (Elliott and Elliott, 1993). In fact, the presence of this channel is thought to be the critical link enabling the hyperexcitability of nociceptive afferents observed in the presence of NaV1.7 mutations associated with erythermalgia (Rush, et al., 2006).

As part of the rationale for focusing their study on NaV1.8, Yamane and colleagues summarize data implicating the involvement of this channel in the hyper-reflexia and hypersensitivity observed following inflammation of visceral structures. For example acetic acid-induced bladder hyper-reflexia is attenuated following antisense knock-down of NaV1.8 (Yoshimura, et al., 2001). Additional evidence that NaV1.8 mediated currents play an important role in visceral hyperalgesia and hyper-reflexia comes from the observations that these currents are increased in sensory neurons 1) innervating the stomach following gastric inflammation (Bielefeldt, et al., 2002), 2) innervating the jejunum/abdominal cavity, following upper gastrointestinal tract infection Nippostrongylus brasiliensis (Hillsley, et al., 2006), and 3) innervating the ileum (Stewart, et al., 2003) and 4) colon (Beyak, et al., 2004) following trinitrobenzene sulphonic acid (TNBS) induced inflammation of these structures. NaV1.8 mediated currents in colonic sensory neurons are increased by inflammatory mediators (Gold, et al., 2002). Furthermore, neuronal hyperexcitability following infection of the jejunum is attenuated in NaV1.8 null mutant mice (Hillsley, et al., 2006) as is the hyperalgesia and nociceptive behavior associated with intracolonic capsaicin (Laird, et al., 2002).

There is also a growing body of evidence in support of a role for NaV1.8 in the hyperexcitability and pain associated with injury to other somatic structures. NaV1.8 current is increased in somatic sensory neurons by a host of proinflammatory mediators including adenosine (Gold, et al., 1996), endothelin (Zhou, et al., 2002), nerve growth factor (Zhang, et al., 2002), prostaglandin E2 (Gold, et al., 1996), serotonin (Cardenas, et al., 1997, Gold, et al., 1996), and TNF-alpha (Jin and Gereau, 2006) utilizing second messenger pathways ranging from PKA (Gold, et al., 1998) to p38 MAPK (Jin and Gereau, 2006). There is even an increase in channel density in painful tooth pulp (Renton, et al., 2005, Warren, et al., In Press). Antisense knock down of NasV1.8 attenuates both the development (Khasar, et al., 1998) and maintenance (Joshi, et al., 2006, Porreca, et al., 1999) of inflammatory hyperalgesia. Importantly, there is also compelling evidence to suggest that the NaV1.8 is critical for the manifestation of neuropathic pain. The channel is sensitized in association with diabetic neuropathy (Hirade, et al., 1999) and accumulates in painful neuromas following traumatic nerve injury (Coward, et al., 2001, Coward, et al., 2000). Interestingly, the manner in which this channel appears to contribute to neuropathic pain changes over time with a role in the uninjured neighbors of injured afferents at early time points (Gold, et al., 2003) and injured afferents at later time points (Coward, et al., 2000). While not tested at later time points, antisense knock-down of the channel can both prevent and reverse hypersensitivity observed following traumatic nerve injury (Gold, et al., 2003). It is important to point out, particularly within the context of the study conducted by Yamane and colleagues, that decreasing NaV1.8 may effectively attenuate visceral hyper-reflexia, even if this channel is not the primary mechanism mediating the increase in excitability. For example, bladder inflammation results in a dramatic increase in the excitability of bladder afferents that appears to reflect a decrease in voltage-gated K+ channels (Yoshimura and de Groat, 1999), yet knocking down NaV1.8 effectively reverses the inflammation-induced hyper-reflexia (Yoshimura, et al., 2001).

While it is clear from the preceding discussion that a selective blocker of VGSCs such as NaV1.7 or NaV1.8 may have tremendous therapeutic potential, such selectivity has been difficult to come by. One major reason for the difficulty in identifying alpha-subunit specific blockers is that there is considerable homology between alpha subunits at sites most logically targeted. For example, the channel pore is effectively and selectively blocked with macromolecules such as tetrodotoxin (TTX) and saxitoxin, yet only a single amino acid distinguishes toxin sensitive (NaV1.1–1.7) from resistant (NaV1.8–1.9) channels in this region (Sivilotti, et al., 1997). Similarly, immobilizing the voltage-sensor can prevent channels from opening, yet compounds such as local anesthetics that utilize such a mechanism are relatively non-selective for channels in the resting or closed state (Gold, et al., 1998). That said, detailed analysis of the mechanisms of local anesthetic actions led to the concept of a state-dependent block, whereby the potency of these compounds depends on the state of the channel (Hille, 1977): these compounds have access to a high affinity site when channels are in an open or inactivated state, while only a low affinity site is accessible to these compounds when channels are in a resting or closed state. Taking advantage of this property, even non-selective compounds such as lidocaine may be used systemically to block channels demonstrating aberrant activity, such as those in the heart responsible for arrhythmias, or those in sensory nerves underlying ongoing pain.

Ralfinamide (NW-1029), the compound employed in the study by Yamane and colleagues, was identified in a screen of potential Na+ channel blockers (Veneroni, et al., 2003). Like local anesthetics, ralfinamide-induced block of VGSCs is state dependent (Stummann, et al., 2005). The potency for block of channels in the inactivated state is up to 7 times higher than channels in a resting state. There is little difference between TTX-sensitive currents and NaV1.8 mediated currents with respect to the potency of ralfinamide for channels in resting or inactivated states. However, this compound appears to selectively facilitate use-dependent block of NaV1.8 channels (Stummann, et al., 2005). This phenomenon appears to reflect a more rapid entry into and a slower recovery from an inactivated state, with more channels residing in an inactivated state with each successive activation of the channels. And it is this difference in the fraction of channels inactivated with each activation that appears to confer the selectivity of ralfinamide. Importantly, ralfinamide was shown to reverse hypersensitivity in animal models of neuropathic and inflammatory pain (Veneroni, et al., 2003).

To further explore the contribution of NaV1.8 to the antinociceptive effects of ralfinamide, Yamane and colleagues characterized the impact of this compound on the excitability of isolated DRG neurons in the presence of TTX. Excitability was assessed with current injection and the number of evoked action potentials was used to monitor the effects of ralfinamide. Subpopulations of neurons were defined by the number of action potentials evoked in response to suprathresold stimuli as tonic (>4 action potential over 600 ms) or phasic (< 4 action potentials over 600 ms). Subpopulations were also defined by responsiveness to the algogenic compound, capsaicin (500 nM).

Three intriguing observations arose from their study. First, ralfinamide preferentially reduced the number of evoked spikes in tonic capsaicin responsive neurons, having a significantly smaller effect on tonic capsaicin unresponsive neurons. Second, substance P selectively increased the number of evoked action potentials in capsaicin responsive neurons. And third, repetitive spiking induced by substance P in capsaicin responsive neurons was selectively attenuated by ralfinamide. These observations are intriguing for at least two reasons. First, they indicate that the properties of NaV1.8 channels are different in capsaicin responsive neurons than in capsaicin unresponsive neurons. Thus, the heterogeneity of sensory neurons is not simply determined by the relative pattern of expression of different proteins (i.e., see (Matzner and Devor, 1992)), but the properties of these proteins as well. The context of a given protein, in this case NaV1.8 influences its properties. Thus, NaV1.8 is subject to use-dependent block, as manifest by a progressive decrease in action potential amplitude in tonic capsaicin responsive neurons. In tonic capsaicin unresponsive neurons, NaV1.8 is subject to little, if any use-dependent block. An important implication of this observation is that it may not only be possible to selectively block a VGSC, but block a subpopulation of these channels most responsible for persistent pain. A subpopulation of capsaicin responses neurons thought to play a particularly important role in persistent pain are referred to as silent or sleeping nociceptors (Schmidt, et al., 1995). While highly speculative, a causal link between the use dependent block observed in Yamane’s study and the action potential slowing which serves as a defining feature of silent nociceptors, would suggest these afferents may be just the population one would want to selectively target for the greatest therapeutic impact.

Another intriguing aspect of the observations of Yamane and colleagues is that the sensitization of capsaicin responsive neurons, involving mechanisms distinct from NaV1.8 (i.e., the block of a voltage-gated K+ channel), conferred therapeutic potential to NaV1.8. That is, the unique feature of NaV1.8 channels in capsaicin responsive neurons appeared to be present even if other channels play a more dominant role in limiting the number of action potentials evoked in response to depolarizing stimuli under “normal” circumstances. Block of these channels, as appears to occur in the presence of persistent inflammation (Dang, et al., 2004, Harriott, et al., 2006, Stewart, et al., 2003, Yoshimura and de Groat, 1999), results in an increase in afferent excitability as well as the emergence of NaV1.8 as an important therapeutic target.

The only perplexing aspect of the Yamane study is the fact that other investigators have not observed the clear distinction between capsaicin responsive and unresponsive neurons with respect to use-dependent block of NaV1.8 mediated currents induced at stimulation frequencies of 0.3 Hz or higher. In one study, use-dependent block of NaV1.8 mediated currents was observed in all DRG neurons studied (Blair and Bean, 2002). In others, no use-dependent block was detected in any DRG neuron studied (Brau and Elliott, 1998, Gold and Thut, 2001). In a more recent study, two populations of DRG neurons, one with and one without use-dependent block of NaV1.8 were described (Choi, et al., 2007). However, in this last study, these two populations were also defined by the presence or absence of isolectin B4 (IB4) binding rather than capsaicin sensitivity. Use-dependent block of NaV1.8 was pronounced in IB4+ neurons, and minimal in the IB4− subpopulation. IB4 is a plant lectin that binds to a cell surface carbohydrate enriched in a subpopulation of sensory neurons with a small cell body diameter (Stucky and Lewin, 1999). This subpopulation of nociceptive DRG neurons tends to share a number of other properties including a distinct termination pattern in the superficial dorsal horn of the spinal cord (Braz, et al., 2005), largely unmyelinated axons and the absence of the neuropeptides calcitonin gene related peptide and substance P (Silverman and Kruger, 1988). Importantly, however, multiple lines of evidence suggest that a significant proportion of both IB4+ and IB4− neurons are capsaicin responsive (Dirajlal, et al., 2003, Flake, et al., 2005, Lu, et al., 2006). A possible explanation for the differences between studies is the existence of variability across ganglia. Yamane and colleagues studied neurons from S1 and L6 ganglia (personal communication) because these are more likely to give rise to innervation of visceral structures. Others have studied neurons from L4 and L5 ganglia (Choi, et al., 2007) that are more likely to give rise to innervation of somatic structures. Given several marked differences between visceral and somatic afferents (i.e., see (Gold and Traub, 2004)), it is possible that the distribution of NaV1.8 with use-dependent block varies according to target of innervation and/or between ganglia. Of course, less interesting explanations like differences in experimental conditions may contribute as well.

Regardless of subpopulation differences, what Yamane and colleagues have again highlighted is the therapeutic potential of a selective blocker of NaV1.8. That such a compound may have finally been discovered is suggested by a recent description of A-803467, a compound that is more than 100 times more selective for NaV1.8 than other VGSCs (Jarvis, et al., 2007). Block of NaV1.8 by A-803467 is state dependent, with inactivated channels blocked at a higher potency than channels in a resting or closed state. Surprisingly, A-803467 did not attenuate postoperative hypersensitivity, serving as a reminder of the importance of context. However, A-803467 did effectively antagonize hypersensitivity associated with nerve injury and persistent inflammation, a therapeutic profile that may still enable an end to a considerable amount of suffering.

Footnotes

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References

1. Akopian AN, Sivilotti L, Wood JN. A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature. 1996;379:257–262. [PubMed]
2. Beyak MJ, Ramji N, Krol KM, Kawaja MD, Vanner SJ. Two TTX-resistant Na+ currents in mouse colonic dorsal root ganglia neurons and their role in colitis-induced hyperexcitability. Am J Physiol Gastrointest Liver Physiol. 2004;287:G845–G855. [PubMed]
3. Bielefeldt K, Ozaki N, Gebhart GF. Mild gastritis alters voltage-sensitive sodium currents in gastric sensory neurons in rats. Gastroenterology. 2002;122:752–761. [PubMed]
4. Black JA, Liu S, Tanaka M, Cummins TR, Waxman SG. Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain. Pain. 2004;108:237–247. [PubMed]
5. Blair NT, Bean BP. Roles of tetrodotoxin (TTX)-sensitive Na+ current, TTX-resistant Na+ current, and Ca2+ current in the action potentials of nociceptive sensory neurons. J Neurosci. 2002;22:10277–10290. [PubMed]
6. Brau ME, Elliott JR. Local anaesthetic effects on tetrodotoxin-resistant Na+ currents in rat dorsal root ganglion neurones [In Process Citation] Eur J Anaesthesiol. 1998;15:80–88. [PubMed]
7. Braz JM, Nassar MA, Wood JN, Basbaum AI. Parallel "pain" pathways arise from subpopulations of primary afferent nociceptor. Neuron. 2005;47:787–793. [PubMed]
8. Cantrell AR, Catterall WA. Neuromodulation of Na+ channels: an unexpected form of cellular plasticity. Nat Rev Neurosci. 2001;2:397–407. [PubMed]
9. Cardenas CG, Del Mar LP, Cooper BY, Scroggs RS. 5HT4 receptors couple positively to tetrodotoxin-insensitive sodium channels in a subpopulation of capsaicin-sensitive rat sensory neurons. J Neurosci. 1997;17:7181–7189. [PubMed]
10. Catterall WA, Goldin AL, Waxman SG. International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev. 2005;57:397–409. [PubMed]
11. Chen Y, Yu FH, Surmeier DJ, Scheuer T, Catterall WA. Neuromodulation of Na+ channel slow inactivation via cAMP-dependent protein kinase and protein kinase C. Neuron. 2006;49:409–420. [PubMed]
12. Choi JS, Dib-Hajj SD, Waxman SG. Differential slow inactivation and use-dependent inhibition of Nav1.8 channels contribute to distinct firing properties in IB4+ and IB4− DRG neurons. J Neurophysiol. 2007;97:1258–1265. [PubMed]
13. Coward K, Aitken A, Powell A, Plumpton C, Birch R, Tate S, Bountra C, Anand P. Plasticity of TTX-sensitive sodium channels PN1 and brain III in injured human nerves. Neuroreport. 2001;12:495–500. [PubMed]
14. Coward K, Jowett A, Plumpton C, Powell A, Birch R, Tate S, Bountra C, Anand P. Sodium channel beta1 and beta2 subunits parallel SNS/PN3 alpha-subunit changes in injured human sensory neurons. Neuroreport. 2001;12:483–438. [PubMed]
15. Coward K, Plumpton C, Facer P, Birch R, Carlstedt T, Tate S, Bountra C, Anand P. Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states. Pain. 2000;85:41–50. [PubMed]
16. Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, Al-Gazali L, Hamamy H, Valente EM, Gorman S, Williams R, McHale DP, Wood JN, Gribble FM, Woods CG. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006;444:894–898. [PubMed]
17. Cummins TR, Aglieco F, Renganathan M, Herzog RI, Dib-Hajj SD, Waxman SG. Nav1.3 sodium channels: rapid repriming and slow closed-state inactivation display quantitative differences after expression in a mammalian cell line and in spinal sensory neurons. J Neurosci. 2001;21:5952–5961. [PubMed]
18. Dang K, Bielefeldt K, Gebhart GF. Gastric ulcers reduce A-type potassium currents in rat gastric sensory ganglion neurons. Am J Physiol Gastrointest Liver Physiol. 2004;286:G573–G579. [PubMed]
19. Dirajlal S, Pauers LE, Stucky CL. Differential response properties of IB(4)-positive and -negative unmyelinated sensory neurons to protons and capsaicin. J Neurophysiol. 2003;89:513–524. [PubMed]
20. Djouhri L, Fang X, Okuse K, Wood JN, Berry CM, Lawson SN. The TTX-resistant sodium channel Nav1.8 (SNS/PN3): expression and correlation with membrane properties in rat nociceptive primary afferent neurons. J Physiol. 2003;550:739–752. [PMC free article] [PubMed]
21. Elliott AA, Elliott JR. Characterization of TTX-sensitive and TTX-resistant sodium currents in small cells from adult rat dorsal root ganglia. J Physiol (Lond) 1993;463:39–56. [PMC free article] [PubMed]
22. Fertleman CR, Baker MD, Parker KA, Moffatt S, Elmslie FV, Abrahamsen B, Ostman J, Klugbauer N, Wood JN, Gardiner RM, Rees M. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron. 2006;52:767–774. [PubMed]
23. Fitzgerald EM, Okuse K, Wood JN, Dolphin AC, Moss SJ. cAmp-dependent phosphorylation of the tetrodotoxin-resistant voltage- dependent sodium channel Sns. J Physiol (Lond) 1999;516:433–446. [PMC free article] [PubMed]
24. Flake NM, Bonebreak DB, Gold MS. Estrogen and inflammation increase the excitability of rat temporomandibular joint afferent neurons. J Neurophysiol. 2005;93:1585–1597. [PMC free article] [PubMed]
25. Gold MS, Levine JD, Correa AM. Modulation of TTX-R INa by PKC and PKA and their role in PGE2-induced sensitization of rat sensory neurons In vitro [In Process Citation] J Neurosci. 1998;18:10345–10355. [PubMed]
26. Gold MS, Reichling DB, Hampl KF, Drasner K, Levine JD. Lidocaine toxicity in primary afferent neurons from the rat. J Pharmacol Exp Ther. 1998;285:413–421. [PubMed]
27. Gold MS, Reichling DB, Shuster MJ, Levine JD. Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current in nociceptors. Proc Natl Acad Sci U S A. 1996;93:1108–1112. [PMC free article] [PubMed]
28. Gold MS, Thut PD. Lithium increases potency of lidocaine-induced block of voltage-gated na(+) currents in rat sensory neurons in vitro. J Pharmacol Exp Ther. 2001;299:705–711. [PubMed]
29. Gold MS, Traub RJ. Cutaneous and colonic rat DRG neurons differ with respect to both baseline and PGE2-induced changes in passive and active electrophysiological properties. J Neurophysiol. 2004;91:2524–2531. [PubMed]
30. Gold MS, Weinreich D, Kim CS, Wang R, Treanor J, Porreca F, Lai J. Redistribution of Na(V)1.8 in uninjured axons enables neuropathic pain. J Neurosci. 2003;23:158–166. [PubMed]
31. Gold MS, Zhang L, Wrigley DL, Traub RJ. Prostaglandin E(2) Modulates TTX-R I(Na) in Rat Colonic Sensory Neurons. J Neurophysiol. 2002;88:1512–1522. [PubMed]
32. Gould HJ, 3rd, England JD, Soignier RD, Nolan P, Minor LD, Liu ZP, Levinson SR, Paul D. Ibuprofen blocks changes in Na v 1.7 and 1.8 sodium channels associated with complete Freund's adjuvant-induced inflammation in rat. J Pain. 2004;5:270–280. [PubMed]
33. Hains BC, Saab CY, Klein JP, Craner MJ, Waxman SG. Altered sodium channel expression in second-order spinal sensory neurons contributes to pain after peripheral nerve injury. J Neurosci. 2004;24:4832–4829. [PubMed]
34. Harriott AM, Dessem D, Gold MS. Inflammation increases the excitability of masseter muscle afferents. Neuroscience. 2006 [PubMed]
35. Herzog RI, Liu C, Waxman SG, Cummins TR. Calmodulin binds to the C terminus of sodium channels Nav1.4 and Nav1.6 and differentially modulates their functional properties. J Neurosci. 2003;23:8261–8270. [PubMed]
36. Hille B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol. 1977;69:497–515. [PMC free article] [PubMed]
37. Hillsley K, Lin JH, Stanisz A, Grundy D, Aerssens J, Peeters PJ, Moechars D, Coulie B, Stead RH. Dissecting the role of sodium currents in visceral sensory neurons in a model of chronic hyperexcitability using Nav1.8 and Nav1.9 null mice. J Physiol. 2006;576:257–267. [PMC free article] [PubMed]
38. Hirade M, Yasuda H, Omatsu-Kanbe M, Kikkawa R, Kitasato H. Tetrodotoxin-resistant sodium channels of dorsal root ganglion neurons are readily activated in diabetic rats. Neuroscience. 1999;90:933–939. [PubMed]
39. Hoyt SB, London C, Gorin D, Wyvratt MJ, Fisher MH, Abbadie C, Felix JP, Garcia ML, Li X, Lyons KA, McGowan E, MacIntyre DE, Martin WJ, Priest BT, Ritter A, Smith MM, Warren VA, Williams BS, Kaczorowski GJ, Parsons WH. Discovery of a novel class of benzazepinone Na(v)1.7 blockers: potential treatments for neuropathic pain. Bioorg Med Chem Lett. 2007;17:4630–4634. [PubMed]
40. Hoyt SB, London C, Ok H, Gonzalez E, Duffy JL, Abbadie C, Dean B, Felix JP, Garcia ML, Jochnowitz N, Karanam BV, Li X, Lyons KA, McGowan E, Macintyre DE, Martin WJ, Priest BT, Smith MM, Tschirret-Guth R, Warren VA, Williams BS, Kaczorowski GJ, Parsons WH. Benzazepinone Na(v)1.7 blockers: Potential treatments for neuropathic pain. Bioorg Med Chem Lett. 2007;17:6172–6177. [PubMed]
41. Isom LL. I. Cellular and molecular biology of sodium channel beta-subunits: therapeutic implications for pain? I. Cellular and molecular biology of sodium channel beta-subunits: therapeutic implications for pain? Am J Physiol Gastrointest Liver Physiol. 2000;278:G349–G353. [PubMed]
42. Jarvis MF, Honore P, Shieh CC, Chapman M, Joshi S, Zhang XF, Kort M, Carroll W, Marron B, Atkinson R, Thomas J, Liu D, Krambis M, Liu Y, McGaraughty S, Chu K, Roeloffs R, Zhong C, Mikusa JP, Hernandez G, Gauvin D, Wade C, Zhu C, Pai M, Scanio M, Shi L, Drizin I, Gregg R, Matulenko M, Hakeem A, Gross M, Johnson M, Marsh K, Wagoner PK, Sullivan JP, Faltynek CR, Krafte DS. A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc Natl Acad Sci U S A. 2007;104:8520–8525. [PMC free article] [PubMed]
43. Jin X, Gereau RWt. Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-alpha. J Neurosci. 2006;26:246–255. [PubMed]
44. Joshi SK, Mikusa JP, Hernandez G, Baker S, Shieh CC, Neelands T, Zhang XF, Niforatos W, Kage K, Han P, Krafte D, Faltynek C, Sullivan JP, Jarvis MF, Honore P. Involvement of the TTX-resistant sodium channel Nav 1.8 in inflammatory and neuropathic, but not post-operative, pain states. Pain. 2006;123:75–82. [PubMed]
45. Khasar SG, Gold MS, Levine JD. A tetrodotoxin-resistant sodium current mediates inflammatory pain in the rat. Neurosci Lett. 1998;256:17–20. [PubMed]
46. Lai J, Porreca F, Hunter JC, Gold MS. Voltage-gated sodium channels and hyperalgesia. Annu Rev Pharmacol Toxicol. 2004;44:371–397. [PubMed]
47. Laird JM, Souslova V, Wood JN, Cervero F. Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS/PN3)-null mice. J Neurosci. 2002;22:8352–8356. [PubMed]
48. Lindia JA, Kohler MG, Martin WJ, Abbadie C. Relationship between sodium channel Na(V)1.3 expression and neuropathic pain behavior in rats. Pain. 2005;117:145–153. [PubMed]
49. Liu C, Cummins TR, Tyrrell L, Black JA, Waxman SG, Dib-Hajj SD. CAP-1A is a novel linker that binds clathrin and the voltage-gated sodium channel Na(v)1.8. Mol Cell Neurosci. 2005;28:636–649. [PubMed]
50. Liu CJ, Dib-Hajj SD, Black JA, Greenwood J, Lian Z, Waxman SG. Direct interaction with contactin targets voltage-gated sodium channel Nav1.9/NaN to the cell membrane. J Biol Chem. 2001;276:46553–46561. [PubMed]
51. Lu SG, Zhang X, Gold MS. Intracellular calcium regulation among subpopulations of rat dorsal root ganglion neurons. J Physiol. 2006;577:169–190. [PMC free article] [PubMed]
52. Matzner O, Devor M. Na+ conductance and the threshold for repetitive neuronal firing. Brain Res. 1992;597:92–98. [PubMed]
53. Nassar MA, Baker MD, Levato A, Ingram R, Mallucci G, McMahon SB, Wood JN. Nerve injury induces robust allodynia and ectopic discharges in Nav1.3 null mutant mice. Mol Pain. 2006;2(33) [PMC free article] [PubMed]
54. Nassar MA, Stirling LC, Forlani G, Baker MD, Matthews EA, Dickenson AH, Wood JN. Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc Natl Acad Sci U S A. 2004;101:12706–12711. [PMC free article] [PubMed]
55. Okuse K, Malik-Hall M, Baker MD, Poon WY, Kong H, Chao MV, Wood JN. Annexin II light chain regulates sensory neuron-specific sodium channel expression. Nature. 2002;417:653–656. [PubMed]
56. Porreca F, Lai J, Bian D, Wegert S, Ossipov MH, Eglen RM, Kassotakis L, Novakovic S, Rabert DK, Sangameswaran L, Hunter JC. A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain. Proc Natl Acad Sci U S A. 1999;96:7640–7644. [PMC free article] [PubMed]
57. Renton T, Yiangou Y, Plumpton C, Tate S, Bountra C, Anand P. Sodium channel Nav1.8 immunoreactivity in painful human dental pulp. BMC Oral Health. 2005;5:5. [PMC free article] [PubMed]
58. Rush AM, Craner MJ, Kageyama T, Dib-Hajj SD, Waxman SG, Ranscht B. Contactin regulates the current density and axonal expression of tetrodotoxin-resistant but not tetrodotoxin-sensitive sodium channels in DRG neurons. Eur J Neurosci. 2005;22:39–49. [PubMed]
59. Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG. A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc Natl Acad Sci U S A. 2006;103:8245–8250. [PMC free article] [PubMed]
60. Sangameswaran L, Delgado SG, Fish LM, Koch BD, Jakeman LB, Stewart GR, Sze P, Hunter JC, Eglen RM, Herman RC. Structure and function of a novel voltage-gated, tetrodoxtoxin-resistant sodium channel specfic to sensory neurons. J Biol Chem. 1996;271:5953–5956. [PubMed]
61. Schmidt R, Schmelz M, Forster C, Ringkamp M, Torebjork E, Handwerker H. Novel classes of responsive and unresponsive C nociceptors in human skin. J Neurosci. 1995;15:333–341. [PubMed]
62. Shah BS, Rush AM, Liu S, Tyrrell L, Black JA, Dib-Hajj SD, Waxman SG. Contactin associates with sodium channel Nav1.3 in native tissues and increases channel density at the cell surface. J Neurosci. 2004;24:7387–7399. [PubMed]
63. Silverman JD, Kruger L. Lectin and Neuropeptide labeling of separate populations of dorsal root ganlion neurons and associated "nociceptor" thin axons in rat testis and cornea whole-mount preparations. Somatosensory Research. 1988;5:259–267. [PubMed]
64. Sivilotti L, Okuse K, Akopian AN, Moss S, Wood JN. A single serine residue confers tetrodotoxin insensitivity on the rat sensory-neuron-specific sodium channel SNS. FEBS Lett. 1997;409:49–52. [PubMed]
65. Stewart T, Beyak MJ, Vanner S. Ileitis modulates potassium and sodium currents in guinea pig dorsal root ganglia sensory neurons. J Physiol. 2003;552:797–807. [PMC free article] [PubMed]
66. Stucky CL, Lewin GR. Isolectin B(4)-positive and -negative nociceptors are functionally distinct. J Neurosci. 1999;19:6497–6505. [PubMed]
67. Stummann TC, Salvati P, Fariello RG, Faravelli L. The anti-nociceptive agent ralfinamide inhibits tetrodotoxin-resistant and tetrodotoxin-sensitive Na+ currents in dorsal root ganglion neurons. Eur J Pharmacol. 2005;510:197–208. [PubMed]
68. Veneroni O, Maj R, Calabresi M, Faravelli L, Fariello RG, Salvati P. Anti-allodynic effect of NW-1029, a novel Na(+) channel blocker, in experimental animal models of inflammatory and neuropathic pain. Pain. 2003;102:17–25. [PubMed]
69. Warren CA, Mok L, Gordon S, Fouad AF, Gold MS. Quantification of neural protein in exterpated tooth pulp. J Endo. In Press.
70. Waxman SG, Dib-Hajj S. Erythermalgia: molecular basis for an inherited pain syndrome. Trends Mol Med. 2005;11:555–562. [PubMed]
71. Waxman SG, Kocsis JD, Black JA. Type III sodium channel mRNA is expressed in embryonic but not adult spinal sensory neurons, and is reexpressed following axotomy. J Neurophysiol. 1994;72:466–470. [PMC free article] [PubMed]
72. Wittmack EK, Rush AM, Hudmon A, Waxman SG, Dib-Hajj SD. Voltage-gated sodium channel Nav1.6 is modulated by p38 mitogen-activated protein kinase. J Neurosci. 2005;25:6621–6630. [PubMed]
73. Yamane H, de Groat WC, Sculptoreanu A. Effects of ralfinamide, a Na+ channel blocker, on firing properties of nociceptive dorsal root ganglion neurons of adult rats. Exp Neurol. 2007 [PMC free article] [PubMed]
74. Yang Y, Wang Y, Li S, Xu Z, Li H, Ma L, Fan J, Bu D, Liu B, Fan Z, Wu G, Jin J, Ding B, Zhu X, Shen Y. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet. 2004;41:171–174. [PMC free article] [PubMed]
75. Yeomans DC, Levinson SR, Peters MC, Koszowski AG, Tzabazis AZ, Gilly WF, Wilson SP. Decrease in inflammatory hyperalgesia by herpes vector-mediated knockdown of Nav1.7 sodium channels in primary afferents. Hum Gene Ther. 2005;16:271–277. [PubMed]
76. Yoshimura N, de Groat WC. Increased excitability of afferent neurons innervating rat urinary bladder after chronic bladder inflammation. J Neurosci. 1999;19:4644–4653. [PubMed]
77. Yoshimura N, Seki S, Novakovic SD, Tzoumaka E, Erickson VL, Erickson KA, Chancellor MB, de Groat WC. The involvement of the tetrodotoxin-resistant sodium channel nav1.8 (pn3/sns) in a rat model of visceral pain. J Neurosci. 2001;21:8690–8696. [PubMed]
78. Yu FH, Westenbroek RE, Silos-Santiago I, McCormick KA, Lawson D, Ge P, Ferriera H, Lilly J, DiStefano PS, Catterall WA, Scheuer T, Curtis R. Sodium channel beta4, a new disulfide-linked auxiliary subunit with similarity to beta2. J Neurosci. 2003;23:7577–7585. [PubMed]
79. Zhang YH, Vasko MR, Nicol GD. Ceramide, a putative second messenger for nerve growth factor, modulates the TTX-resistant Na(+) current and delayed rectifier K(+) current in rat sensory neurons. J Physiol. 2002;544:385–402. [PMC free article] [PubMed]
80. Zhou Z, Davar G, Strichartz G. Endothelin-1 (ET-1) selectively enhances the activation gating of slowly inactivating tetrodotoxin-resistant sodium currents in rat sensory neurons: a mechanism for the pain-inducing actions of ET-1. J Neurosci. 2002;22:6325–6330. [PubMed]
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