Involvement of Na+ channels in pain pathways

Baker, Mark D.; Wood, John N.

doi:10.1016/s0165-6147(00)01585-6

Cited by 199 publications

(125 citation statements)

References 41 publications

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“…Defined nociceptor subtypes have been termed C-fiber (C-) or Aδ-fiber (A-) mechanoheat nociceptors (MHNs), mechanical nociceptors (MNs), mechanically insensitive (MI) or sensitive afferents, and mechanoheat-cold nociceptors [5,6]. The molecular properties of DRG neurons have been extensively studied, including their expression of various receptors and ion channels such as neuropeptide Y (NPY) receptors [7], MAS-related G-protein-coupled receptors (MRGPRs) [8,9], voltage-gated Na + channels [10], transient receptor potential (TRP) channels [11,12], ATP receptors [13], acid-sensing ion channels (ASICs) [14,15] and tyrosine kinase receptors (TRKs) [16]. Gene expression profiles of DRG tissue have been also analyzed by microarray and RNA-sequencing (RNA-seq) techniques [17,18].…”

Section: Introductionmentioning

confidence: 99%

Somatosensory neuron types identified by high-coverage single-cell RNA-sequencing and functional heterogeneity

et al. 2015

Cell Res

396

432

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Section: Introductionmentioning

confidence: 99%

Somatosensory neuron types identified by high-coverage single-cell RNA-sequencing and functional heterogeneity

et al. 2015

Cell Res

396

432

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“…Na v 1.7 falls into the TTX-sensitive category, showing an IC 50 of 2 nM for TTX. There has been a resurgence of interest recently in sodium channels as potential analgesic drug targets based on antisense and null mutant mice studies (31,32). Interpreting null mutant phenotypes can be problematic, because developmental compensatory mechanisms may occur, and, occasionally, embryonic or perinatal death precludes behavioral studies.…”

Section: Resultsmentioning

confidence: 99%

Nociceptor-specific gene deletion reveals a major role for Na_v1.7 (PN1) in acute and inflammatory pain

Nassar

Stirling

Forlani

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

611

514

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Nine voltage-gated sodium channels are expressed in complex patterns in mammalian nerve and muscle. Three channels, Nav1.7, Nav1.8, and Na v1.9, are expressed selectively in peripheral damage-sensing neurons. Because there are no selective blockers of these channels, we used gene ablation in mice to examine the function of Nav1.7 (PN1) in pain pathways. A global Nav1.7-null mutant was found to die shortly after birth. We therefore used the Cre؊loxP system to generate nociceptor-specific knockouts. Na v1.8 is only expressed in peripheral, mainly nociceptive, sensory neurons. We knocked Cre recombinase into the Na v1.8 locus to generate heterozygous mice expressing Cre recombinase in Nav1.8-positive sensory neurons. Crossing these animals with mice where Na v1.7 exons 14 and 15 were flanked by loxP sites produced nociceptor-specific knockout mice that were viable and apparently normal. These animals showed increased mechanical and thermal pain thresholds. Remarkably, all inflammatory pain responses evoked by a range of stimuli, such as formalin, carrageenan, complete Freund's adjuvant, or nerve growth factor, were reduced or abolished. A congenital pain syndrome in humans recently has been mapped to the Na v1.7 gene, SCN9A. Dominant Na v1.7 mutations lead to edema, redness, warmth, and bilateral pain in human erythermalgia patients, confirming an important role for Na v1.7 in inflammatory pain. Nociceptor-specific gene ablation should prove useful in understanding the role of other broadly expressed genes in pain pathways.

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“…In nociceptive DRG neurons, tetrodotoxin-sensitive (TTX-S) currents are carried by Na v 1.1, -1.2, -1.6, and -1.7 subtypes, with a minor contribution from Na v 1.3 (2). In the presence of TTX and when recording conditions that inactivate Na v 1.9 but not Na v 1.8 were used, MrVIB was Ͼ10-fold more potent at blocking TTX-R currents than TTX-S Na ϩ currents (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Unfortunately, VGSC inhibitors show limited selectivity for pain versus other sensory and motor neurotransmission pathways in the periphery, despite possessing functional selectivity associated with activitydependent block (1). Among the VGSC ␣-subunit subtypes known to mediate action potential generation in mammals, Na v 1.8 is a particularly promising candidate for development of subtype-selective VGSC therapeutics for persistent pain (1,2). VGSC subtypes exhibit differential tissue distribution, but only Na v 1.8 is expressed exclusively by primary afferent neurons (3,4).…”

mentioning

confidence: 99%

μO-conotoxin MrVIB selectively blocks Na _v 1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits

Ekberg

Jayamanne

Vaughan

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

180

143

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The tetrodotoxin-resistant voltage-gated sodium channel (VGSC) Na v1.8 is expressed predominantly by damage-sensing primary afferent nerves and is important for the development and maintenance of persistent pain states. Here we demonstrate that O-conotoxin MrVIB from Conus marmoreus displays substantial selectivity for Nav1.8 and inhibits pain behavior in models of persistent pain. In rat sensory neurons, submicromolar concentrations of MrVIB blocked tetrodotoxin-resistant current characteristic of Na v1.8 but not Nav1.9 or tetrodotoxin-sensitive VGSC currents. MrVIB blocked human Na v1.8 expressed in Xenopus oocytes with selectivity at least 10-fold greater than other VGSCs. In neuropathic and chronic inflammatory pain models, allodynia and hyperalgesia were both reduced by intrathecal infusion of MrVIB (0.03-3 nmol), whereas motor side effects occurred only at 30-fold higher doses. In contrast, the nonselective VGSC blocker lignocaine displayed no selectivity for allodynia and hyperalgesia versus motor side effects. The actions of MrVIB reveal that VGSC antagonists displaying selectivity toward Na v1.8 can alleviate chronic pain behavior with a greater therapeutic index than nonselective antagonists. electrophysiology ͉ pain model ͉ dorsal root ganglia ͉ allodynia ͉ ␦-conotoxin

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Involvement of Na+ channels in pain pathways

Cited by 199 publications

References 41 publications

Somatosensory neuron types identified by high-coverage single-cell RNA-sequencing and functional heterogeneity

Somatosensory neuron types identified by high-coverage single-cell RNA-sequencing and functional heterogeneity

Nociceptor-specific gene deletion reveals a major role for Na_v1.7 (PN1) in acute and inflammatory pain

μO-conotoxin MrVIB selectively blocks Na _v 1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits

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Involvement of Na+ channels in pain pathways

Cited by 199 publications

References 41 publications

Somatosensory neuron types identified by high-coverage single-cell RNA-sequencing and functional heterogeneity

Somatosensory neuron types identified by high-coverage single-cell RNA-sequencing and functional heterogeneity

Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain

μO-conotoxin MrVIB selectively blocks Na v 1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits

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Nociceptor-specific gene deletion reveals a major role for Na_v1.7 (PN1) in acute and inflammatory pain

μO-conotoxin MrVIB selectively blocks Na _v 1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits