PAIN�

153 (2012) 1985–1986

w w w . e l s e v i e r . c o m / l o c a t e / p a i n

Commentary

Nav(1.8)igating the maze of sensory function

Back in January 1996, mainly through the use of anticonvulsantdrugs, sodium channel blockade was already a precedented mech-anism in neuropathic pain, however, the cloning of the sensory neu-ronal specific, TTX resistant sodium channel Nav1.8 signalled amajor turning point in pain research and drug discovery [2]. Wenow know that there are nine Nav subtypes, of which Nav1.6,Nav1.7, Nav1.8 and Nav1.9 are highly expressed in nociceptive sen-sory neurons, both on cell bodies and at nerve terminals [11].

In the absence of truly selective pharmacological tools, the painresearch field has assembled a wide array of sodium channel molec-ular tools such as antisense reagents, selective antibodies and evermore sophisticated transgenic mice strains. Immunocytochemistrycombined with electrophysiology and transgenic knockout orknockdown studies have identified Nav1.3, Nav1.7, Nav1.8 andNav1.9 as major contributors to neuropathic and inflammatory pain[6].

Nav1.8 has been long thought of and used as a marker of pre-dominantly nociceptive small diameter dorsal root ganglion(DRG) neurons. Some dogmas can hold firm and up to now, itwas thought that less than 15% of large DRG neurons expressedNav1.8 [1,3], although Renganathan et al. [13] as well as Djouhriet al. [7] had suggested a more widespread expression beyondsmall diameter DRG neurons. In this issue of Pain, Shields et al. pro-vide strong evidence that up to 40% of large diameter, low thresh-old mechanoreceptor (LTM) DRG neurons express functionalNav1.8 channels [14]. The electrophysiology studies in this manu-script, which showed that activation and fast inactivation of theTTX-r current were similar in both small and large DRG neuronsare convincing and in agreement with published literature [6,13].This finding is doubly significant, first because Nav1.8 has beenand still is one of the top targets in pain research and discoveryand second it has been used widely as a molecular tool to definenociceptive DRG neurons [9].

So, will there be consequences for Nav1.8 as a pain target? First,Shields et al. [14] show that muscular afferents do not express anyNav1.8 channels, which is good news in terms of possible side ef-fects of Nav1.8 blockers on proprioception and indirectly on bal-ance. Second, Abrahamsen et al. [1] reported that destroyingNav1.8-positive DRG neurons using diphtheria toxin did not affectlow threshold mechanosensation and acute noxious heat responses.These results appear surprising given the widespread expression ofNav1.8 now suggested by Shields et al. [14] It is possible of course,that a loss of 40% of LTMs is not enough to have a quantifiable effecton mouse somatosensation, although harder to imagine that acuteheat pain sensation in mice could be supported by the 10% of noci-ceptors not expressing Nav1.8.

Third, the present study finds that Nav1.8 is enriched in VGLUT3-positive C-LTMs, which are responsible for gentle touch sensationand contribute to injury-induced mechanical hypersensitivity in

0304-3959/$36.00 � 2012 International Association for the Study of Pain. Published byhttp://dx.doi.org/10.1016/j.pain.2012.06.008

rodent neuropathic pain models. Assuming of course that humanspossess VGLUT3-positive C-LTMs (which is yet to be demonstrated),this might add to the therapeutic benefit of a Nav1.8 blocker. On theother hand a significant downside could be the potential loss of sometouch sensation. The recent finding that Nav1.8 is expressed in mo-tor nerves deficient in myelin protein zero that are typical of theCharcot-Marie-Tooth disease phenotype, suggests that Nav1.8blockers may have beneficial effects in therapeutic areas other thanpain [10].

On a more cautious note, Nav1.8 channels have also turned up inan unexpected and potentially problematic location, the humanheart [12,4,8]. Genome wide association studies have shown thatNav1.8 is involved in the duration of the electrocardiogram PR inter-val (a measure of atrial and atrioventricular nodal conduction).Prolongation of the PR interval increases the risk of atrial fibrillation,the most common cardiac sustained arrhythmia. At least onenon-synonymous single nucleotide polymorphism in Nav1.8(rs6795970) is strongly correlated with prolonged PR interval. Tele-metric electrocardiographic recordings in conscious mice treatedwith the selective Nav1.8 channel blocker A-803467 show thatblockade of Nav1.8 increases both QRS and PR intervals significantly[15].

The ultimate significance of Shields et al.’s finding depends onwhether data obtained in mice will translate to humans. In supportof the findings in this manuscript, Coward et al. [5] have shown thatNav1.8 is expressed on all types of DRG neurons in man. Therefore,the main problem posed by the wider than expected expression ofNav1.8 in sensory nerves could be that blockers of the channelmight have subtle effects on human physiology that cannot be mea-sured in mice. Marketed drugs such as carbamazepine, lacosamideand lamotrigine, which all have a predominant mechanism of actionagainst voltage gated sodium channels, show little or no selectivityfor different Nav subtypes. The overriding adverse effects of thesecompounds are CNS side effects such as dizziness, nausea and atax-ia, rather than any peripherally mediated effects. Such adverseevents are almost certainly a consequence of blocking the mainCNS sodium channel subtypes, such as Nav1.2 and Nav1.6. We willonly learn if there are consequences of this more widespread DRGexpression, once the next generation of more selective Nav1.8blocking compounds, which avoid hitting the CNS Nav channels,are tested in patients with chronic pain. We can expect to see datafrom such selective molecules in the next few years, however giventhe presence of the Nav1.8 channel in the heart, extra vigilance willalso be required to monitor cardiovascular function.

Finally, as Shield et al. rightly point out, their data have greatrelevance to the significant number of studies that have usedNav1.8-Cre technology to derive conditional knockout mice, espe-cially to the interpretation of the unexpected phenotypes that havebeen observed. As pain researchers plan their next knock-out

Elsevier B.V. All rights reserved.

1986 Commentary / PAIN�

153 (2012) 1985–1986

mouse studies, they will have to think more carefully about whichtechnology they employ, especially if their study is directed to-wards function of their chosen gene in small diameter nociceptiveneurons.

Conflict of interest statement

The authors have no conflict of interest regarding thiscommentary.

References

[1] Abrahamsen B, Zhao J, Asante CO, Cendan CM, Marsh S, Martinez-Barbera JP,Nassar MA, Dickenson AH, Wood JN. The cell and molecular basis ofmechanical, cold, and inflammatory pain. Science 2008;321:702–5.

[2] Akopian AN, Sivilotti L, Wood JN. A tetrodotoxin-resistant voltage-gatedsodium channel expressed by sensory neurons. Nature 1996;379:257–62.

[3] Amaya F, Decosterd I, Samad TA, Plumpton C, Tate S, Mannion RJ, Costigan M,Woolf CJ. Diversity of expression of the sensory neuron-specific TTX-resistantvoltage-gated sodium ion channels SNS and SNS2. Mol Cell Neurosci2000;15:331–42.

[4] Chambers JC, Zhao J, Terracciano CM, Bezzina CR, Zhang W, Kaba R,Navaratnarajah M, Lotlikar A, Sehmi JS, Kooner MK, et al. Genetic variationin SCN10A influences cardiac conduction. Nat Genet 2010;42:149–52.

[5] 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 humanpain states. PAIN� 2000;85:41–50.

[6] Dib-Hajj SD, Black JA, Waxman SG. Voltage-gated sodium channels:therapeutic targets for pain. Pain Med 2009;10:1260–9.

[7] Djouhri L, Fang X, Okuse K, Wood JN, Berry CM, Lawson S. The TTX-resistantsodium channel Nav1.8 (SNS/PN3): expression and correlation with membraneproperties in rat nociceptive primary afferent neurons. J Physiol (Lond)2003;550:739–52.

[8] Holm H, Gudbjartsson DF, Arnar DO, Thorleifsson G, Thorgeirsson G,Stefansdottir H, Gudjonsson SA, Jonasdottir A, et al. Several common variantsmodulate heart rate, PR interval and QRS duration. Nat Genet 2010;42:117–22.

[9] Liu M, Wood JN. The roles of sodium channels in nociception: implications formechanisms of neuropathic pain. Pain Med 2011;12:S93–9.

[10] Moldovan M, Alvarez S, Pinchenko V, Klein D, Nielsen FC, Wood JN, Martini R,Krarup C. Na(v)1.8 channelopathy in mutant mice deficient for myelin proteinzero is detrimental to motor axons. Brain 2011;134:585–601.

[11] Persson AK, Black JA, Gasser A, Cheng X, Fischer TZ, Waxman SG. Sodium-calcium exchanger and multiple sodium channel isoforms in intra-epidermalnerve terminals. Mol Pain 2010;6:84.

[12] Pfeufer A, van Noord C, Marciante KD, Arking DE, Larson MG, Smith AV,Tarasov KV, Müller M, Sotoodehnia N, Sinner MF, et al. Genome-wideassociation study of PR interval. Nat Genet 2010;42:153–9.

[13] Renganathan M, Cummins TR, Hormuzdiar WN, Waxman SG. Alpha-SNSproduces the slow TTXresistant sodium current in large cutaneous afferentDRG neurons. J Neurophysiol 2000;84:710–8.

[14] Shields SD, Ahn YS, Yang Y, Han C, Seal RP, Wood JN, Waxman SG, Dib-Hajj SD.Nav1.8 expression is not restricted to nociceptors in mouse peripheral nervoussystem. PAIN� 2012;153:2017–30.

[15] Sotoodehnia N, Isaacs A, de Bakker PI, Dörr M, Newton-Cheh C, Nolte IM, vander Harst P, et al. Common variants in 22 loci are associated with QRS durationand cardiac ventricular conduction. Nat Genet 2010;42:1068–76.

Simon Tate⇑Dominique Derjean

François RugieroConvergence Pharmaceuticals Ltd.,

Babraham Research Campus,Cambridge CB22 3AT, UK

⇑ Tel.: +44 (0)1223 755 501; fax: +44 (0)1223 497114.E-mail address: simon.tate@convergencepharma.com (S. Tate)