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  • Print publication year: 2013
  • Online publication date: December 2013

Chapter 6 - Pathophysiology of neuropathic pain: voltage-gated sodium and calcium channels

from Section 2 - The Condition of Neuropathic Pain


1. GoldMS, GebhartGF.Nociceptor sensitization in pain pathogenesis. Nat Med 2010;16:1248–57.
2. TheileJW, CumminsTR.Recent developments regarding voltage-gated sodium channel blockers for the treatment of inherited and acquired neuropathic pain syndromes. Front Pharmacol 2011;2:54.
3. Dib-HajjSD, CumminsTR, BlackJA, WaxmanSG.Sodium channels in normal and pathological pain. Annu Rev Neurosci 2010;33:325–47.
4. FischerTZ, WaxmanSG.Familial pain syndromes from mutations of the NaV1.7 sodium channel. Ann N Y Acad Sci 2010;1184:196–207.
5. Vargas-AlarconG, Alvarez-LeonE, FragosoJM, et al. A SCN9A gene-encoded dorsal root ganglia sodium channel polymorphism associated with severe fibromyalgia. BMC Musculoskelet Disord 2010;13:23.
6. WangSY, CalderonJ, Kuo WangG.Block of neuronal Na+ channels by antidepressant duloxetine in a state-dependent manner. Anesthesiology 2010;113:655–65.
7. DabbyR.Pain disorders and erythromelalgia caused by voltage-gated sodium channel mutations. Curr Neurol Neurosci Rep 2012;12:76–83.
8. EstacionM, HartyTP, ChoiJS, et al. A sodium channel gene SCN9A polymorphism that increases nociceptor excitability. Ann Neurol 2009;66:862–6.
9. ReimannF, CoxJJ, BelferI, et al. Pain perception is altered by a nucleotide polymorphism in SCN9A. Proc Natl Acad Sci USA 2010;107:5148–53.
10. HanC, HoeijmakersJGJ, AhnHS, et al. Nav1.7-related small fiber neuropathy: impaired slow-inactivation and DRG neuron hyperexcitability. Neurology 2012;78:1635–43.
11. FaberCG, HoeijmakersJG, AhnHS, et al. Gain of function Naν1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 2010;71:26–39.
12. CowardK, PlumptonC, FacerP, et al. Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states. Pain 2000;85:41–50.
13. CowardK, JowettA, PlumptonC, et al. Sodium channel beta1 and beta2 subunits parallel SNS/PN3 alpha-subunit changes in injured human sensory neurons. Neuroreport 2001;12:483–8.
14. BertaT, PoirotO, PertinM, et al. Transcriptional and functional profiles of voltage-gated Na(+) channels in injured and non-injured DRG neurons in the SNI model of neuropathic pain. Mol Cell Neurosci 2008;37:196–208.
15. ChattopadhyayM, MataM, FinkDJ.Vector-mediated release of GABA attenuates pain-related behaviors and reduces Na(V)1.7 in DRG neurons. Eur J Pain 2011;15:913–20.
16. ChattopadhyayM, ZhouZ, HaoS, MataM, FinkDJ.Reduction of voltage gated sodium channel protein in DRG by vector mediated miRNA reduces pain in rats with painful diabetic neuropathy. Mol Pain 2012;8:17.
17. WangW, GuJ, LiYQ, TaoYX.Are voltage-gated sodium channels on the dorsal root ganglion involved in the development of neuropathic pain?Mol Pain 2011;7:16.
18. RushAM, CumminsTR, WaxmanSG. Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. J Physiol 2007;579: 1–14.
19. ZimmermannK, LefflerA, BabesA, et al. Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures. Nature 2007;447:855–8.
20. LiuM, WoodJN. The roles of sodium channels in nociception: implications for mechanisms of neuropathic pain. Pain Med 2011;12 (Suppl 3):S93–9.
21. CumminsTR, SheetsPL, WaxmanSG.The roles of sodium channels in nociception: implications for mechanisms of pain. Pain 2007;131:243–57.
22. JoshiSK, MikusaJP, HernandezG, et al. 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.
23. RuangsriS, LinA, MulpuriY, et al. Relationship of axonal voltage-gated sodium channel 1.8 (NaV1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J Biol Chem 2011;286:39836–47.
24. SunW, MiaoB, WangXC, et al. Reduced conduction failure of the main axon of polymodal nociceptive C-fibres contributes to painful diabetic neuropathy in rats. Brain 2012;135:359–75.
25. BrackenburyWJ, IsomLL.Na channel β subunits: overachievers of the ion channel family. Front Pharmacol 2011;2:53.
26. ChahineM, O’LearyME.Regulatory role of voltage-gated Na channel β subunits in sensory neurons. Front Pharmacol 2011;2:70.
27. CatterallWA, Perez-ReyesE, SnutchTP, StriessnigJ.International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacol Rev 2005;57:411–25.
28. Perez-ReyesE.Molecular physiology of low-voltage-activated T-type calcium channels. Physiol Rev 2003;83:117–61.
29. DolphinAC.Beta subunits of voltage-gated calcium channels. J Bioenerg Biomembr 2003;35:599–620.
30. KlugbauerN, LacinovaL, MaraisE, HobomM, HofmannF.Molecular diversity of the calcium channel alpha2delta subunit. J Neurosci 1999;19:684–91.
31. EvansAR, NicolGD, VaskoMR.Differential regulation of evoked peptide release by voltage-sensitive calcium channels in rat sensory neurons. Brain Res 1996;712:265–73.
32. SmithMT, CabotPJ, RossFB, RobertsonAD, LewisRJ.The novel N-type calcium channel blocker, AM336, produces potent dose-dependent antinociception after intrathecal dosing in rats and inhibits substance P release in rat spinal cord slices. Pain 2002;96:119–27.
33. ChaplanSR, PogrelJW, YakshTL.Role of voltage-dependent calcium channel subtypes in experimental tactile allodynia. J Pharmacol Exp Ther 1994;269:1117–23.
34. OhnamiS, TanabeM, ShinoharaS, et al. Role of voltage-dependent calcium channel subtypes in spinal long-term potentiation of C-fiber-evoked field potentials. Pain 2011;152:623–31.
35. SnutchTP.Targeting chronic and neuropathic pain: the N-type calcium channel comes of age. NeuroRx 2005;2:662–70.
36. StaatsPS, YearwoodT, CharapataSG, et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. J Am Med Assoc 2004;291:63–70.
37. BellTJ, ThalerC, CastiglioniAJ, HeltonTD, LipscombeD.Cell-specific alternative splicing increases calcium channel current density in the pain pathway. Neuron 2004;41:127–38.
38. AltierC, DaleCS, KisilevskyAE, et al. Differential role of N-type calcium channel splice isoforms in pain. J Neurosci 2007;27:6363–73.
39. BrittainJM, DuarteDB, WilsonSM, et al. Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca(2) channel complex. Nat Med 2011;17:822–9.
40. ZamponiGW, LewisRJ, TodorovicSM, ArnericSP, SnutchTP.Role of voltage-gated calcium channels in ascending pain pathways. Brain Res Rev 2009;60:84–9.
41. IkedaH, StarkJ, FischerH, et al. Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science 2006;312:1659–62.
42. TodorovicSM, Jevtovic-TodorovicV, MeyenburgA, et al. Redox modulation of T-type calcium channels in rat peripheral nociceptors. Neuron 2001;31:75–85.
43. TodorovicSM, MeyenburgA, Jevtovic-TodorovicV.Redox modulation of peripheral T-type Ca(2+) channels in vivo: alteration of nerve injury-induced thermal hyperalgesia. Pain 2004;109:328–39.
44. NelsonMT, WooJ, KangHW, et al. Reducing agents sensitize C-type nociceptors by relieving high-affinity zinc inhibition of T-type calcium channels. J Neurosci 2007;27:8250–60.
45. DolmetschRE, PajvaniU, FifeK, SpottsJM, GreenbergME.Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science 2001;294:333–9.
46. FossatP, DobremezE, Bouali-BenazzouzR, et al. Knockdown of L calcium channel subtypes: differential effects in neuropathic pain. J Neurosci 2010;30:1073–85.
47. FavereauxA, ThoumineO, Bouali-BenazzouzR, et al. Bidirectional integrative regulation of Cav1.2 calcium channel by microRNA miR-103: role in pain. Embo J 2011;30:3830–41.
48. HildebrandME, SmithPL, BladenC, et al. A novel slow-inactivation-specific ion channel modulator attenuates neuropathic pain. Pain 2011;152:833–43.
49. EmeryEC, YoungGT, BerrocosoEM, ChenL, McNaughtonPA.HCN2 ion channels play a central role in inflammatory and neuropathic pain. Science 2011;333:1462–6.