Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Molecular Pain
Published in: Molecular Pain 1/2012

Open Access 01-12-2012 | Research

Expression of Nav1.7 in DRG neurons extends from peripheral terminals in the skin to central preterminal branches and terminals in the dorsal horn

Authors: Joel A Black, Noémie Frézel, Sulayman D Dib-Hajj, Stephen G Waxman

Published in: Molecular Pain | Issue 1/2012

Login to get access

Abstract

Background

Sodium channel Nav1.7 has emerged as a target of considerable interest in pain research, since loss-of-function mutations in SCN9A, the gene that encodes Nav1.7, are associated with a syndrome of congenital insensitivity to pain, gain-of-function mutations are linked to the debiliting chronic pain conditions erythromelalgia and paroxysmal extreme pain disorder, and upregulated expression of Nav1.7 accompanies pain in diabetes and inflammation. Since Nav1.7 has been implicated as playing a critical role in pain pathways, we examined by immunocytochemical methods the expression and distribution of Nav1.7 in rat dorsal root ganglia neurons, from peripheral terminals in the skin to central terminals in the spinal cord dorsal horn.

Results

Nav1.7 is robustly expressed within the somata of peptidergic and non-peptidergic DRG neurons, and along the peripherally- and centrally-directed C-fibers of these cells. Nav1.7 is also expressed at nodes of Ranvier in a subpopulation of Aδ-fibers within sciatic nerve and dorsal root. The peripheral terminals of DRG neurons within skin, intraepidermal nerve fibers (IENF), exhibit robust Nav1.7 immunolabeling. The central projections of DRG neurons in the superficial lamina of spinal cord dorsal horn also display Nav1.7 immunoreactivity which extends to presynaptic terminals.

Conclusions

The expression of Nav1.7 in DRG neurons extends from peripheral terminals in the skin to preterminal central branches and terminals in the dorsal horn. These data support a major contribution for Nav1.7 in pain pathways, including action potential electrogenesis, conduction along axonal trunks and depolarization/invasion of presynaptic axons. The findings presented here may be important for pharmaceutical development, where target engagement in the right compartment is essential.
Appendix
Available only for authorised users
Literature
1.
Momin A, Wood JN: Sensory neuron voltage-gated sodium channels as analgesic drug targets. Curr Opin Neurobiol 2008,18(4):383–388. 10.1016/j.conb.2008.08.017CrossRefPubMed
2.
Dib-Hajj SD, Black JA, Waxman SG: Voltage-gated sodium channels: therapeutic targets for pain. Pain Med 2009,10(7):1260–1269. 10.1111/j.1526-4637.2009.00719.xCrossRefPubMed
3.
Dib-Hajj SD, Cummins TR, Black JA, Waxman SG: Sodium channels in normal and pathological pain. Annu Rev Neurosci 2010, 33: 325–347. 10.1146/annurev-neuro-060909-153234CrossRefPubMed
4.
Clare JJ: Targeting ion channels for drug discovery. Discov Med 2010,9(46):253–260.PubMed
5.
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(4):397–409. 10.1124/pr.57.4.4CrossRefPubMed
6.
Liu M, Wood JN: The roles of sodium channels in nociception: implications for mechanisms of neuropathic pain. Pain Med 2011,12(Suppl 3):S93-S99.CrossRefPubMed
7.
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(7121):894–898. 10.1038/nature05413CrossRefPubMed
8.
Ahmad S, Dahllund L, Eriksson AB, Hellgren D, Karlsson U, Lund PE, Meijer IA, Meury L, Mills T, Moody A, Morinville A, Morten J, O’donnell D, Raynoschek C, Salter H, Rouleau GA, Krupp JJ: A stop codon mutation in SCN9A causes lack of pain sensation. Hum Mol Genet 2007,16(17):2114–2121. 10.1093/hmg/ddm160CrossRefPubMed
9.
Goldberg YP, MacFarlane J, MacDonald ML, Thompson J, Dube MP, Mattice M, Fraser R, Young C, Hossain S, Pape T, Payne B, Radomski C, Donaldson G, Ives E, Cox J, Younghusband HB, Green R, Duff A, Boltshauser E, Grinspan GA, Dimon JH, Sibley BG, Andria G, Toscano E, Kerdraon J, Bowsher D, Pimstone SN, Samuels ME, Sherrington R, Hayden MR: Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations. Clin Genet 2007,71(4):311–319. 10.1111/j.1399-0004.2007.00790.xCrossRefPubMed
10.
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(3):171–174. 10.1136/jmg.2003.012153PubMedCentralCrossRefPubMed
11.
Dib-Hajj SD, Rush AM, Cummins TR, Hisama FM, Novella S, Tyrrell L, Marshall L, Waxman SG: Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons. Brain 2005,128(Pt 8):1847–1854.CrossRefPubMed
12.
Han C, Rush AM, Dib-Hajj SD, Li S, Xu Z, Wang Y, Tyrrell L, Wang X, Yang Y, Waxman SG: Sporadic onset of erythermalgia: a gain-of-function mutation in Nav1.7. Ann Neurol 2006,59(3):553–558. 10.1002/ana.20776CrossRefPubMed
13.
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 USA 2006,103(21):8245–8250. 10.1073/pnas.0602813103PubMedCentralCrossRefPubMed
14.
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(5):767–774. 10.1016/j.neuron.2006.10.006CrossRefPubMed
15.
Dib-Hajj SD, Estacion M, Jarecki BW, Tyrrell L, Fischer TZ, Lawden M, Cummins TR, Waxman SG: Paroxysmal extreme pain disorder M1627K mutation in human Nav1.7 renders DRG neurons hyperexcitable. Mol Pain 2008,19(4):37.CrossRef
16.
Cheng X, Dib-Hajj SD, Tyrrell L, Wright DA, Fischer TZ, Waxman SG: Mutations at opposite ends of the DIII/S4-S5 linker of sodium channel Na V 1.7 produce distinct pain disorders. Mol Pain 2010, 6: 24. 10.1186/1744-8069-6-24PubMedCentralCrossRefPubMed
17.
Estacion M, Han C, Choi JS, Hoeijmakers JG, Lauria G, Drenth JP, Gerrits MM, Dib-Hajj SD, Faber CG, Merkies IS, Waxman SG: Intra- and interfamily phenotypic diversity in pain syndromes associated with a gain-of-function variant of Nav1.7. Mol Pain 2011, 7: 9. 10.1186/1744-8069-7-9CrossRef
18.
Faber CG, Hoeijmakers JG, Ahn HS, Cheng X, Han C, Choi JS, Estacion M, Lauria G, Vanhoutte EK, Gerrits MM, Dib-Hajj S, Drenth JP, Waxman SG, Merkies IS: Gain of function Naν1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 2012,71(1):26–39. 10.1002/ana.22485CrossRefPubMed
19.
Han C, Hoeijmakers JG, Ahn HS, Zhao P, Shah P, Lauria G, Gerrits MM, Te Morsche RH, Dib-Hajj SD, Drenth JP, Faber CG, Merkies IS, Waxman SG: Nav1.7-related small fiber neuropathy: Impaired slow-inactivation and DRG neuron hyperexcitability. Neurology 2012,78(21):1635–1643. 10.1212/WNL.0b013e3182574f12CrossRefPubMed
20.
Klugbauer N, Lacinova L, Flockerzi V, Hofmann F: Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells. EMBO J 1995,14(6):1084–1090.PubMedCentralPubMed
21.
Cummins TR, Howe JR, Waxman SG: Slow closed-state inactivation: a novel mechanism underlying ramp currents in cells expressing the hNE/PN1 sodium channel. J Neurosci 1998,18(23):9607–9619.PubMed
22.
Herzog RI, Cummins TR, Ghassemi F, Dib-Hajj SD, Waxman SG: Distinct repriming and closed-state inactivation kinetics of Nav1.6 and Nav1.7 sodium channels in mouse spinal sensory neurons. J Physiol 2003,551(Pt 3):741–750.PubMedCentralCrossRefPubMed
23.
Rush AM, Cummins TR, Waxman SG: Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. J Physiol 2007,579(Pt 1):1–14.PubMedCentralCrossRefPubMed
24.
Black JA, Dib-Hajj S, McNabola K, Jeste S, Rizzo MA, Kocsis JD, Waxman SG: Spinal sensory neurons express multiple sodium channel alpha-subunit mRNAs. Mol Brain Res 1996,43(1–2):117–131.CrossRefPubMed
25.
Toledo-Aral JJ, Moss BL, He ZJ, Koszowski AG, Whisenand T, Levinson SR, Wolf JJ, Silos-Santiago I, Halegoua S, Mandel G: Identification of PN1, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons. Proc Natl Acad Sci USA 1997,94(4):1527–1532. 10.1073/pnas.94.4.1527PubMedCentralCrossRefPubMed
26.
Djouhri L, Newton R, Levinson SR, Berry CM, Carruthers B, Lawson SN: Sensory and electrophysiological properties of guinea-pig sensory neurones expressing Nav 1.7 (PN1) Na+ channel α subunit protein. J Physiol 2003,546(Pt 2):565–576.PubMedCentralCrossRefPubMed
27.
Fukuoka T, Kobayashi K, Yamanaka H, Obata K, Dai Y, Noguchi K: Comparative study of the distribution of the alpha-subunits of voltage-gated sodium channels in normal and axotomized rat dorsal root ganglion neurons. J Comp Neurol 2008,510(2):188–206. 10.1002/cne.21786CrossRefPubMed
28.
Ahn H-S, Black JA, Zhao P, Tyrrell L, Waxman SG, Dib-Hajj SD: Nav1.7 is the predominant sodium channel in rodent olfactory sensory neurons. Mol Pain 2011, 7: 32. 10.1186/1744-8069-7-32PubMedCentralCrossRefPubMed
29.
Weiss J, Pyrski M, Jacobi E, Bufe B, Willnecker V, Schick B, Zizzari P, Gossage SJ, Greer CA, Leinders-Zufall T, Woods CG, Wood JN, Zufall F: Loss-of-function mutations in sodium channel Nav1.7 cause anosmia. Nature 2011, 472: 186–190. 10.1038/nature09975PubMedCentralCrossRefPubMed
30.
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(1):39–49. 10.1111/j.1460-9568.2005.04186.xCrossRefPubMed
31.
Persson AK, Black JA, Gasser A, Cheng X, Fischer TZ, Waxman SG: Sodium-calcium exchanger and multiple sodium channel isoforms in intra-epidermal nerve terminals. Mol Pain 2010, 6: 84.PubMedCentralPubMed
32.
Morinville A, Fundin B, Meury L, Juréus A, Sandberg K, Krupp J, Ahmad S, O’Donnell D: Distribution of the voltage-gated sodium channel Na(v)1.7 in the rat: expression in the autonomic and endocrine systems. J Comp Neurol 2007,504(6):680–689. 10.1002/cne.21484CrossRefPubMed
33.
Dib-Hajj SD, Cummins TR, Black JA, Waxman SG: From genes to pain: Nav 1.7 and human pain disorders. Trends Neurosci 2007,30(11):555–563. 10.1016/j.tins.2007.08.004CrossRefPubMed
34.
Goldstein ME, House SB, Gainer H: NF-L and peripherin immunoreactivities define distinct classes of rat sensory ganglion cells. J Neurosci Res 1991,30(1):92–104. 10.1002/jnr.490300111CrossRefPubMed
35.
Michael GJ, Priestley JV: Differential expression of the mRNA for the vanilloid receptor subtype 1 in cells of the adult rat dorsal root and nodose ganglia and its downregulation by axotomy. J Neurosci 1999,19(5):1844–1854.PubMed
36.
Snider WD, McMahon SB: Tackling pain at the source: new ideas about nociceptors. Neuron 1998,20(4):629–632. 10.1016/S0896-6273(00)81003-XCrossRefPubMed
37.
Einheber S, Zanazzi G, Ching W, Scherer S, Milner TA, Peles E, Salzer JL: The axonal membrane protein Caspr, a homologue of neurexin IV, is a component of the septate-like paranodal junctions that assemble during myelination. J Cell Biol 1997,139(6):1495–1506. 10.1083/jcb.139.6.1495PubMedCentralCrossRefPubMed
38.
Zylka MJ, Rice FL, Anderson DJ: Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 2005,45(1):17–25. 10.1016/j.neuron.2004.12.015CrossRefPubMed
39.
Valtorta F, Tarelli FT, Campanati L, Villa A, Greengard P: Synaptophysin and synapsin I as tools for the study of the exo-endocytotic cycle. Cell Biol Int Rep 1989,13(12):1023–1038. 10.1016/0309-1651(89)90017-9CrossRefPubMed
40.
Mullen RJ, Buck CR, Smith AM: NeuN, a neuronal specific nuclear protein in vertebrates. Development 1992,116(1):201–211.PubMed
41.
Harper AA, Lawson SN: Electrical properties of rat dorsal root ganglion neurones with different peripheral nerve conduction velocities. J Physiol 1985, 359: 47–63.PubMedCentralCrossRefPubMed
42.
Drenth JP, te Morsche RH, Guillet G, Taieb A, Kirby RL, Jansen JB: SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels. J Invest Dermatol 2005,124(6):1333–1338. 10.1111/j.0022-202X.2005.23737.xCrossRefPubMed
43.
Nyström B, Hagbarth KE: Microelectrode recordings from transected nerves in amputees with phantom limb pain. Neurosci Lett 1981,27(2):211–216. 10.1016/0304-3940(81)90270-6CrossRefPubMed
44.
Devor M, Govrin-Lippmann R: Axoplasmic transport block reduces ectopic impulse generation in injured peripheral nerves. Pain 1983,16(1):73–85. 10.1016/0304-3959(83)90087-8CrossRefPubMed
45.
Kretschmer T, Happel LT, England JD, Nguyen DH, Tiel RL, Beuerman RW, Kline DG: Accumulation of PN1 and PN3 sodium channels in painful human neuroma-evidence from immunocytochemistry. Acta Neurochir (Wien) 2002,144(8):803–810. 10.1007/s00701-002-0970-1CrossRef
46.
Bird EV, Robinson PP, Boissonade FM: Na(v)1.7 sodium channel expression in human lingual nerve neuromas. Arch Oral Biol 2007,52(5):494–502. 10.1016/j.archoralbio.2006.11.011CrossRefPubMed
47.
Black JA, Nikolajsen L, Kroner K, Jensen TS, Waxman SG: Multiple sodium channel isoforms and mitogen-activated protein kinases are present in painful neuromas. Ann Neurol 2008,64(6):644–653. 10.1002/ana.21527CrossRefPubMed
48.
Stamboulian S, Choi JS, Ahn HS, Chang YW, Tyrrell L, Black JA, Waxman SG, Dib-Hajj SD: ERK1/2 mitogen-activated protein kinase phosphorylates sodium channel Na(v)1.7 and alters its gating properties. J Neurosci 2010,30(5):1637–1647. 10.1523/JNEUROSCI.4872-09.2010CrossRefPubMed
49.
Persson AK, Gasser A, Black JA, Waxman SG: Nav1.7 accumulates and co-localizes with phosphorylated ERK1/2 within transected axons in early experimental neuromas. Exp Neurol 2011,230(2):273–279. 10.1016/j.expneurol.2011.05.005CrossRefPubMed
50.
Hong S, Morrow TJ, Paulson PE, Isom LL, Wiley JW: Early painful diabetic neuropathy is associated with differential changes in tetrodotoxin-sensitive and -resistant sodium channels in dorsal root ganglion neurons in the rat. J Biol Chem 2004,279(28):29341–29350. 10.1074/jbc.M404167200PubMedCentralCrossRefPubMed
51.
Chattopadhyay M, Zhou Z, Hao S, Mata M, Fink DJ: Reduction of voltage gated sodium channel protein in DRG by vector mediated miRNA reduces pain in rats with painful diabetic neuropathy. Mol Pain 2012,8(1):17. 10.1186/1744-8069-8-17PubMedCentralCrossRefPubMed
52.
Sun W, Miao B, Wang XC, Duan JH, Wang WT, Kuang F, Xie RG, Xing JL, Xu H, Song XJ, Luo C, Hu SJ: Reduced conduction failure of the main axon of polymodal nociceptive C-fibres contributes to painful diabetic neuropathy in rats. Brain 2012,135(Pt 2):359–375.CrossRefPubMed
53.
Chattopadhyay M, Mata M, Fink DJ: Continuous delta-opioid receptor activation reduces neuronal voltage-gated sodium channel (NaV1.7) levels through activation of protein kinase C in painful diabetic neuropathy. J Neurosci 2008,28(26):6652–6658. 10.1523/JNEUROSCI.5530-07.2008PubMedCentralCrossRefPubMed
54.
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(3):237–247. 10.1016/j.pain.2003.12.035CrossRefPubMed
55.
Gould HJ, England JD, Soignier RD, Nolan P, Minor LD, Liu ZP, Levinson SR, Paul D: Ibuprofen blocks changes in Nav 1.7 and Nav1.8 sodium channels associated with complete Freund’s adjuvant-induced inflammation in rat. J Pain 2004,5(5):270–280. 10.1016/j.jpain.2004.04.005CrossRefPubMed
56.
Strickland IT, Martindale JC, Woodhams PL, Reeve AJ, Chessell IP, McQueen DS: Changes in the expression of NaV1.7, NaV1.8 and NaV1.9 in a distinct population of dorsal root ganglia innervating the rat knee joint in a model of chronic inflammatory joint pain. Eur J Pain 2008,12(5):564–572. 10.1016/j.ejpain.2007.09.001CrossRefPubMed
57.
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(2):271–277. 10.1089/hum.2005.16.271CrossRefPubMed
58.
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 USA 2004,101(34):12706–12711. 10.1073/pnas.0404915101PubMedCentralCrossRefPubMed
59.
Minett MS, Nassar MA, Clark AK, Passmore G, Dickenson AH, Wang F, Malcangio M, Wood JN: Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons. Nat Commun 2012, 3: 791.PubMedCentralCrossRefPubMed
60.
Shields SD, Cheng X, Uceyler N, Sommer C, Dib-Hajj S, Waxman SG: Sodium channel Nav1.7 is essential for lowering heat pain threshold after burn injury. J Neurosci 2012,32(32):10819–10832. 10.1523/JNEUROSCI.0304-12.2012CrossRefPubMed
61.
Caldwell JH, Schaller KL, Lasher RS, Peles E, Levinson SR: Sodium channel Na(v)1.6 is localized at nodes of ranvier, dendrites, and synapses. Proc Natl Acad Sci USA 2000,97(10):5616–20. 10.1073/pnas.090034797PubMedCentralCrossRefPubMed
62.
Cain DM, Khasabov SG, Simone DA: Response properties of mechanoreceptors and nociceptors in mouse glabrous skin: an in vivo study. J Neurophysiol 2001,85(4):1561–74.PubMed
Metadata
Title
Expression of Nav1.7 in DRG neurons extends from peripheral terminals in the skin to central preterminal branches and terminals in the dorsal horn
Authors
Joel A Black
Noémie Frézel
Sulayman D Dib-Hajj
Stephen G Waxman
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Molecular Pain / Issue 1/2012
Electronic ISSN: 1744-8069
DOI
https://doi.org/10.1186/1744-8069-8-82

Other articles of this Issue 1/2012

Molecular Pain 1/2012 Go to the issue

Research

Warmth suppresses and desensitizes damage-sensing ion channel TRPA1

Research

Neurotrophic factor changes in the rat thick skin following chronic constriction injury of the sciatic nerve

Research

Characterization of neuronal intrinsic properties and synaptic transmission in layer I of anterior cingulate cortex from adult mice

Research

L type Ca2+ channel blockers prevent oxaliplatin-induced cold hyperalgesia and TRPM8 overexpression in rats

Research

PAPupuncture has localized and long-lasting antinociceptive effects in mouse models of acute and chronic pain

Research

The cytochrome P450 inhibitor, ketoconazole, inhibits oxidized linoleic acid metabolite-mediated peripheral inflammatory pain